Two percent of patients with X-linked intellectual disability (XLID) exhibit loss-of-function mutations in the enzyme, ZDHHC9. One of the main anatomical deficits observed in these patients is a decrease in corpus callosum volume and a concurrent disruption in white matter integrity. In this study, we demonstrate that deletion of Zdhhc9 in mice disrupts the balance of mature oligodendrocyte subtypes within the corpus callosum. While overall mature oligodendrocyte numbers are unchanged, there is a marked increase in MOL5/6 cells that are enriched in genes associated with cell adhesion and synapses, and a concomitant decrease in MOL2/3 cells that are enriched in genes associated with myelination. In line with this, we observed a decrease in the density of myelinated axons and disruptions in myelin compaction in the corpus callosum of Zdhhc9 knockout mice. RNA sequencing and proteomic analysis further revealed a reduction in genes and proteins essential for lipid metabolism, cholesterol synthesis, gene expression, and myelin compaction, offering insights into the underlying mechanisms of the pathology. These findings reveal a previously underappreciated and fundamental role for ZDHHC9 and protein palmitoylation in regulating oligodendrocyte subtype determination and myelinogenesis, offering mechanistic insights into the deficits observed in white matter volume in patients with mutations in ZDHHC9.

Cancer has high mortality rate and occupies second position among major diseases. Despite extensive research and therapies, in every nook and corner of the world, death rate is increasing exponentially. Hallmarks of cancer are benchmarks of cancer cells describing the fundamental principle and capabilities of the cells transforming from normal to malignant tumour. One of the major ones among them is the deregulation of cellular metabolism or metabolic reprogramming, involving alterations in glucose and lipid metabolism. Progressive research in this area has visualized the vital role of lncRNAs in lipid metabolism with respect to AML. lncRNAs involve in various cellular processes and also contribute for significant functions of the cell like chromatin remodelling, transcriptional activation and repression, gene regulation, immune response, cell differentiation, and cell cycle regulation, in addition to oncogenic processes such as proliferation, angiogenesis, migration, and apoptosis. Structural similarities are observed among mRNAs and lncRNAs in terms of poly A-tail and 5' cap however protein-coding regions are lacking. A large body of evidence has shown that lncRNAs directly or indirectly mediate lipid metabolism by activating downstream genes. Considering their potential involvement in leukemia, these lncRNAs can be explored and considered as biomarkers for therapeutics, prognosis, and diagnosis. The present review is planned to summarize the functional classification of lncRNAs, the role of lipid metabolism in cancer, different lncRNAs involved in leukemia, and different cancer types related to lipid metabolism.

Ubiquitin-specific peptidase 24 (USP24), a deubiquitinating enzyme, regulates protein stability by removing ubiquitin. This study investigates the role of UPS24 in lipid metabolism, inflammation, and fibrosis. It also explores the effect of targeting USP24 on metabolic disorders, focusing on high-fat diet (HFD)-induced obesity and liver diseases.

This study utilized CRISPR/Cas9 to create functional knockout mice (USP24C1695A) and treated HFD-fed mice with USP24 inhibitor (USP24-i-101). The effects of USP24 inhibition or knockout on 3T3-L1 derived adipocytes, primary hepatocytes, hepatic stellate cells, and murine hepatocyte cell line AML12 (alpha mouse liver 12) cells were assessed with RNA-sequencing. Molecular mechanisms and the interaction between USP24 and PKA-Cα were studied with co-immunoprecipitation. Downstream signaling pathways involving CREB, SREBP1, PPARγ, and C/EBPβ, as well as USP24 role in liver inflammation and fibrosis, were studied using western blot and real-time PCR. Clinical and animal tissue samples were examined with immunohistochemistry to identify the correlations between USP24 and metabolic-associated liver diseases.

Knockout or inhibition of USP24 reduced body weight, lipid accumulation, inflammation, and fibrosis in HFD-fed mice. The expression of genes related to lipogenesis, inflammation, and fibrosis was downregulated in USP24C1695A mice and those treated with USP24 inhibitor (USP24-i-101). USP24 inhibition decreased lipid droplet accumulation in adipocytes and hepatocytes, suppressed inflammation in hepatocytes and AML12 cells, and reduced fibrosis in hepatic stellate cells. Mechanistically, USP24 expression was upregulated by PKA activation during adipocyte differentiation, leading to increased PKA-Cα stability and CREB phosphorylation, which promoted lipogenic gene expression. Free fatty acids (FFA) increased USP24 expression, activating NF-κB and TGFβ pathways to induce inflammation (Cox2) and fibrosis (α-SMA). USP24 was highly expressed in patients with metabolic dysfunction-associated steatohepatitis (MASH) and correlated with Cox2 and α-SMA levels.

Arctigenin, a natural lignan from Arctium lappa L., exhibits potent antifibrotic activity, yet its molecular mechanisms remain unclear. Endoplasmic reticulum (ER) stress is known to promote hepatic stellate cell (HSC) activation and liver fibrosis. This study investigates the therapeutic potential of arctigenin in HSC activation through ER stress modulation. Primary rat HSCs were activated (3-7 days) and treated with tunicamycin (ER stress inducer) or 4-PBA (ER stress inhibitor). Arctigenin attenuated ER stress markers (e.g., GRP78) and suppressed the expression of fibrotic marker α-SMA in ER stress-challenged activating (day 3) and activated (day 7) HSCs. Arctigenin restored lipid homeostasis by modulation of both lipogenesis (via Dgat2 and Ppar-γ upregulation) and lipolysis (suppression via ATGL inhibition). ER stress activated ER-associated degradation (ERAD), triggering the formation of small lipid droplets (LD). Arctigenin normalized the ERAD activity, thereby rescuing LD integrity and suppressing HSC activation. Our findings demonstrate that arctigenin mitigates HSC activation by suppressing ER stress and restoring lipid homeostasis via modulating ERAD-mediated lipid dysregulation. As a dietary and medicinal compound, arctigenin emerges as a promising therapeutic candidate for liver fibrosis.

In recent years, metabolic reprogramming has emerged as a significant breakthrough in elucidating the onset and progression of gastrointestinal (GI) malignancies. As central regulatory hubs for lipid metabolism, sterol regulatory element binding proteins (SREBPs) integrate dietary metabolic signals and carcinogenic stimuli through subtype-specific mechanisms, thereby promoting malignant tumour phenotypes. In this review, we first present the molecular background, structural characteristics, and posttranscriptional regulatory networks associated with SREBPs. We subsequently describe a systematic analysis of the distinct activation patterns of SREBPs in liver, gastric, colorectal, and other gastrointestinal cancers. Furthermore, we explore targeted intervention strategies for different SREBP subtypes, including small molecule inhibitors (such as fatostatin, which inhibits SREBP cleavage), natural compounds (such as berberine, which modulates the AMPK/mTOR pathway), and statin-mediated inhibition of the mevalonic acid pathway. These strategies may enhance tumour cell sensitivity to chemotherapeutic agents (such as 5-FU, gezil, and tabine) and improve the response to synergistic chemoradiotherapy by reversing adaptive metabolic resistance driven by the tumour microenvironment. Through this review, we hope to provide new insights into precise interventions targeting various subtypes of the SREBP molecule.

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Adipocyte hypertrophy, driven by lipid accumulation, is crucial in the development of obesity. Wild blueberry (WB; Vaccinium angustifolium) (poly)phenols (PPs) metabolites may modulate adipogenesis and the development of obesity. This study examines WB PP metabolites' effects on lipid accumulation, lipid metabolism, and oxidative stress in mature 3T3-L1 adipocytes. Differentiated 3T3-L1 adipocytes were treated for 48 h with free fatty acids (FFAs; oleic/palmitic acid 750 µM, 2:1 ratio) and WB-derived PPs, including ferulic acid (FA), isoferulic acid (IA), vanillic acid (VA), and syringic acid (SA) at physiological and supra-physiological concentrations. Assessments included lipid accumulation, glycerol release, and markers of lipid metabolism (sterol regulatory element-binding protein 1c [SREBP-1], fatty acid synthase [FASN], FAB4) and oxidative stress (DNA damage, 8-hydroxy 2-deoxyguanosine [8OHdG], nuclear erythroid factor 2-related factors 2 (NRF2), heme oxygenase 1 [HO-1]). FFAs significantly increased lipid accumulation, glycerol release, and FASN levels, while reducing HO-1 levels, without affecting other markers. WB PP metabolites did not reduce lipid accumulation, but IA and VA reduced FASN levels (-25% and -26%; p < 0.05), and SA improved HO-1 levels (+150%; p < 0.05). Despite the different effects observed, the findings obtained under our experimental conditions seem to suggest that IA, VA, and SA may modulate lipid metabolism and oxidative stress markers. However, further studies are fundamental to corroborate the findings obtained and support the contribution of these BB PPs metabolites and other compounds in the prevention and management of obesity.

Coenzyme Q10 (CoQ10) is a natural antioxidant and plays a vital role in the energy production of animal cells; however, its physiological and biochemical properties in fish are unclear.

The current experiment was investigated to explore the effects of dietary CoQ10 on growth performance and biochemical and physiological attributes of rainbow trout (Oncorhynchus mykiss).

A 56-day feeding trial was conducted with 5 experimental diets supplemented with CoQ10 concentrations at 0, 25, 50, 100 and 200 mg kg-1 of diet and fed to 400 rainbow trout (10 ± 0.1 g, initial body weight).

Dietary supplementation with CoQ10, especially at the highest dietary level, significantly improved the feed conversion ratio, final body weight and lipid and protein efficiency ratio of fish (p < 0.05). Moreover, the fish carcass protein and lipid content significantly increased with supplementation of 200 mg CoQ10 kg-1 diet (p < 0.05). The blood serum levels of triglycerides (TGs), cholesterol (CHO) and uric acid significantly reduced, whereas albumin, total protein, high-density lipoprotein and lymphocyte count increased with supplementation of 200 mg CoQ10 kg-1 diet (p < 0.05). Administration of 100 mg CoQ10 kg-1 diet significantly reduced the liver gene expression of sterol regulatory element-binding protein1 (SREBP1), whereas supplementation with 200 mg CoQ10 kg-1 diet increased muscle gene expression of SREBP1 (p < 0.05). However, there were negative associations and correlations between blood TGs and CHO levels with liver and muscle SREBP1 gene expression.

Overall, dietary supplementation of CoQ10, particularly at the levels of 100-200 mg kg-1 of diet, can improve growth performance and health in rainbow trout by modifying blood metabolites and SREBP1 gene expression.

In diabetes mellitus, dysregulated glucose and lipid metabolism lead to diabetic cardiomyopathy (DCM) by imparting pathological myocardial remodeling and cellular injury. Accelerated glycation, oxidative stress, and activated inflammatory pathways culminate in cardiac fibrosis and hypertrophy in DCM. The regulatory effects of l-Arginine (L-Arg) have been elucidated in the pathological changes of DCM, including myocardial fibrosis, hypertrophy, and apoptosis, by inhibiting glycation and oxidative stress-induced inflammation. Disturbed L-Arg metabolism and decreased intracellular L-Arg pool are correlated with the progression of DCM; therefore, L-Arg supplementation has been prescribed for various cardiovascular dysfunctions. This review expands the therapeutic potential of L-Arg supplementation in DCM by elucidating its molecular mechanism of action and exploring potential clinical outcomes.

Existing literatures on the potential impact of soy protein consumption on kidney function present conflicting findings. In this study, a meta-analysis has been conducted to assess the impact of soy protein consumption in comparison to animal protein consumption among individuals with chronic kidney disease (CKD).

A structured electronic search was conducted on Medline, EMBASE, and Cochrane Library for randomized controlled trials published up to March 2024. The outcome measures were serum creatinine (SCR), triglyceride (TG), total cholesterol (TC), calcium (Ca), C-reactive protein, proteinuria, high-density lipoprotein (HDL), low-density lipoprotein (LDL), uric acid (UA) and phosphorus concentrations. Mean differences were calculated for net changes using random-effects models.

Eighteen trials with a total of 522 participants were included in this systematic review. The results showed that consumption of soy protein led to a significant decrease in total cholesterol, LDL, and proteinuria levels. The average reduction was  - 20.55 mg/dL (95% CI  - 38.25,  - 2.85 mg/dL) for total cholesterol (P = 0.02),  - 8.26 mg/dL (95% CI  - 13.35,  - 3.17 mg/dL; P = 0.001) for LDL and  - 140.53 (95% CI  - 205.83,  - 75.23 mg/day) for proteinuria. No statistically significant impact was observed on serum creatinine, triglycerides, calcium, C-reactive protein, HDL, uric acid, or phosphorus levels.

The findings of the meta-analysis showed a potential protective impact of soy protein intake on hyperlipidemia and proteinuria in CKD patients. It is important to note that the evidence presented may be of limited accuracy due to relatively small number of trials and participants.

Fatty acid metabolism plays a critical role in regulating immune cell function, including B cells, which are central to humoral immunity and the pathogenesis of autoimmune diseases. Emerging evidence suggests that fatty acid metabolism influences B cell development, activation, differentiation, and antibody production, thereby impacting B cell-related autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS). In this review, we discuss the mechanisms by which fatty acid metabolism modulates B cell biology, including energy provision, membrane composition, and signaling pathways. We highlight how alterations in fatty acid synthesis, oxidation, and uptake affect B cell function and contribute to autoimmune pathogenesis. Additionally, we explore the therapeutic potential of targeting fatty acid metabolism in B cells to treat autoimmune diseases. Understanding the interplay between fatty acid metabolism and B cell immunity may provide novel insights into the development of precision therapies for B cell-mediated autoimmune disorders.

Gonadal testosterone stimulates skeletal muscle anabolism and contributes to sexually differentiated adipose distribution through incompletely understood mechanisms. Observations in humans and animal models have indicated a major role for androgen receptor (AR) in mediating sex differences in body composition throughout the lifespan. Traditional surgical, genetic and pharmacological studies have tested systemic actions of circulating androgens, and more recent transgenic approaches have allowed for tests of AR gene function in specific androgen responsive niches contributing to body composition, including: skeletal muscle and surrounding interstitial cells, white and brown adipose, as well as trabecular and cortical bone. Less well understood is how these functions of gonadal androgens interact with exercise. Here, we summarize the understood mechanisms of action of AR and its interactions with exercise, specifically on outcomes of body composition and muscle function, and the global- and tissue-specific role of AR in regulating skeletal muscle, adipose, and bone morphology. Additionally, we describe the known effects of androgen and AR manipulation on female body composition, muscle morphology, and sport performance, while highlighting a need for greater inclusion of female subjects in human and animal muscle physiology and endocrinology research.

Myxococcota is a phylum of sterol-producing bacteria. They exhibit a clade depth for sterol biosynthesis unparalleled in the bacterial domain and produce sterols of a biosynthetic complexity that rivals eukaryotes. Additionally, the sterol biosynthesis pathways found in this phylum have been proposed as a potential source for sterol biosynthesis in the last eukaryotic common ancestor, lending evolutionary importance to our understanding of this pathway in Myxococcota. However, sterol production has only been characterized in a few species, and outstanding questions about the evolutionary history of this pathway remain. Here, we identify two myxobacteria, Minicystis rosea and Sandaracinus amylolyticus, capable of cholesterol biosynthesis. These two myxobacteria possess a cholesterol biosynthesis pathway that differs in both the ordering and enzymes involved in biosynthesis compared with Enhygromyxa salina, a myxobacterium previously demonstrated to produce cholesterol, as well as the canonical pathways found in eukaryotes. We characterize an alternative bacterial reductase responsible for performing C-24 reduction, further delineating bacterial cholesterol production from eukaryotes. Finally, we examine the distribution and phylogenetic relationships of sterol biosynthesis proteins across both cultured and uncultured Myxococcota species, providing evidence for multiple acquisition events and instances of both horizontal and vertical transfer at the family level. Altogether, this work further demonstrates the capacity of myxobacteria to synthesize eukaryotic sterols but with an underlying diversity in the biochemical reactions that govern sterol synthesis, suggesting a complex evolutionary history and refining our understanding of how myxobacterial cholesterol production relates to their eukaryotic counterparts.

Sterols are essential and ubiquitous lipids in eukaryotes, but their significance in bacteria is less understood. Sterol production in Myxococcota, a phylum of developmentally complex predatory bacteria, has provided insight into novel sterol biochemistry and prompted discussion regarding the evolution of this pathway within both the eukaryotic and bacterial domains. Here, we characterize cholesterol biosynthesis in two myxobacteria, providing evidence for distinct pathway organization and identifying a unique protein responsible for C-24 reduction. We couple these results with the phylogenomic analysis of sterol biosynthesis within Myxococcota, revealing a complicated evolutionary history marked by vertical and horizontal transfer. This suggests a mosaic acquisition of this pathway in Myxococcota and highlights the complex role myxobacteria may have had in sterol transfer to eukaryotes.

Anti-inflammatory herbal formulations are common in traditional Chinese medicine for clearing heat and detoxifying; however, the specific active components and their mechanisms remain unclear.

This study investigates the role of Sitosterol in alleviating perianal inflammation and its underlying mechanisms.

Sitosterol was identified as a key active ingredient through the TCMSP database. Its structure was analyzed using PubChem, target genes were explored with STITCH, and KEGG pathways related to Srebf2 were revealed by STRING. An animal model of perianal inflammation was induced with 75 % acetic acid and treated with Sitosterol, water, normal saline, or antibiotics. The effects on gut microbiota were assessed using 16S rRNA sequencing, and inflammation was evaluated through HE stains, IHC, and TUNEL assays. In vitro, LPS-treated Caco-2 cells were used to measure proliferation, apoptosis, and cytokine levels, with PPAR pathway involvement examined using GW6471.

Sitosterol emerged as the primary active ingredient targeting Srebf2, with KEGG analysis highlighting the PPAR signaling pathway. In rats, Sitosterol reduced weight loss, inflammatory cell infiltration, edema, and vasodilation in perianal tissue. Additionally, it decreased PCNA levels, increased apoptosis, and elevated serum levels of IL-1β, IL-6, and TNF-α, particularly at high doses compared to antibiotics. Sitosterol also restored gut microbiota. Srebf2 knockdown improved tissue conditions and modulated cytokine levels, effects that were countered by GW6471. In LPS-treated Caco-2 cells, Sitosterol reversed reductions in cell viability and proliferation and modulated the expression of proteins and cytokines.

Sitosterol restores gut microbiota composition and further alleviates perianal inflammation in rats by inhibiting Srebf2 expression and activating the PPAR signaling pathway.

Selective nuclear export inhibitor selinexor (SEL) represents a promising therapeutic strategy for relapsed/refractory multiple myeloma (RRMM). But its mechanisms of action as well as factors that influence therapeutic responses have not been fully characterized yet. In this study we employed catTFRE proteomics technique to profile changes in nuclear abundance of activated transcription factors (TFs)/co-factors (TCs) in myeloma cells following SEL treatment. We found that pharmacological inhibition of exportin-1 (XPO1) by SEL leads to a significant nuclear accumulation of Lipin1 in NCI-H929 cells. Nuclear-localized Lipin1 acted as a transcriptional cofactor that suppressed the transcriptional activity of SREBPs. By performing subcellular localization analysis, molecular docking, co-immunoprecipitation and other assays, we demonstrated that Lipin1 was subjected to XPO1-dependent nuclear export. We demonstrated that SEL downregulated the expression of key lipogenesis-related genes regulated by SREBPs including FASN, SCD, DHCR24 and FDPS, leading to reduced fatty acid and cholesterol synthesis in MM cell lines and primary CD138+ cells. Using shRNA-mediated knockdown assays, we elucidated the critical role of Lipin1 in mediating the inhibitory effects of SEL on the SREBPs pathway and its contribution to SEL sensitivity both in vitro and in murine xenograft models. In conclusion, we reveal a novel mechanism by which SEL downregulates cellular lipid biosynthesis, thereby inhibiting the proliferation of myeloma cells. This study highlights the critical role of Lipin1 in the anti-myeloma effects of SEL, suggesting its potential as a biomarker for identifying patients who are most likely to benefit from SEL-based therapies.

Retinol-binding protein 4 (RBP4) has emerged as a critical adipokine involved in the pathophysiology of metabolic and cardiovascular diseases. Beyond its classical role in retinol transport, RBP4 influences insulin resistance, inflammation, lipid metabolism, mitochondrial function, and cellular apoptosis in both skeletal and cardiac muscles. Elevated levels of RBP4 are associated with obesity, type 2 mellitus diabetes, and cardiovascular diseases, making it a potential biomarker and therapeutic target. This comprehensive review elucidates the molecular mechanisms by which RBP4 affects skeletal and cardiac muscle physiology. We discuss its clinical implications as a biomarker for disease risk and progression, explore therapeutic strategies targeting RBP4, and highlight future research directions. Understanding the multifaceted roles of RBP4 could pave the way for novel interventions against metabolic and cardiovascular disorders.

Feeding low crude protein (LCP) diets supplemented with crystalline amino acids improves environmental and welfare parameters of broilers. However, increased body fat contents in broilers fed LCP diets have become a concern. Black soldier fly larvae oil (BSFLO), rich in lauric acid, has been reported to inhibit lipogenesis and reduce body fat. A 3 × 2 factorial experiment was conducted to evaluate the effect of BSFLO on performance, blood biochemistry, carcass quality, fat metabolism gene expression, and litter quality in broilers fed protein-reduced diets. A total of 288 broilers were divided into 6 treatments: three CP levels (200, 185, or 170 g/kg; high [HCP], medium [MCP], or low [LCP]) and two oil sources (BSFLO and Crude Palm Oil [CPO]), with 6 replicate pens of 8 birds each. Results showed a 15 g/kg CP reduction had no effect on body weight and feed intake (P > 0.05) but increased FCR (P = 0.001). A 30 g/kg CP significantly reduced the body weight and feed intake with inferior FCR (P < 0.05). However, negative effect of low CP diets on FCR was mitigated by BSFLO (P = 0.008). Reducing CP by 30 g/kg increased fat pads (P = 0.033), whereas BSFLO reduced fat pads (P = 0.049) at all three CP levels. Protein-reduced diets increased blood cholesterol (P = 0.002), HDL (P < 0.001), and LDL (P = 0.002). BSFLO decreased blood triglyceride (P = 0.026) and cholesterol (P < 0.001). Reducing 30 g/kg CP increased meat cooking loss (P = 0.035), while BSFLO decreased cooking loss (P < 0.001). BSFLO increased meat protein (P < 0.001) and decreased cholesterol (P = 0.003). The inclusion of BSFLO in protein-reduced diet down-regulated the gene expression of FAS, ACC, SREBP-1, and HMGR in broilers (P < 0.001). Reducing CP levels decreased litter pH (P = 0.011), nitrogen (P < 0.001), ammonia (P < 0.001) and moisture (P = 0.018). The study concludes that BSFLO reduced body fat by down-regulating the lipogenesis gene expression. In addition, BSFLO enhanced feed efficiency in broilers fed protein-reduced diet.

Metabolic dysfunction associated steatohepatitis (MASH), previously referred to as nonalcoholic steatohepatitis (NASH), has emerged as one of the leading indications for liver transplantation in the United States. The disease is associated with increased cardiovascular mortality in patients with early-stage liver fibrosis and a heightened risk of hepatic complications in those with advanced fibrosis. Despite its growing prevalence and significant healthcare burden, there were no approved drugs to treat this chronic disease. In March 2024, Resmetirom, a selective thyroid hormone receptor-beta agonist, became the first drug to receive FDA approval for the treatment of patients with MASH and fibrosis stages F2/F3. This accelerated approval was granted based on significantly higher rates of MASH resolution and fibrosis.

This review summarizes the current literature on the mechanism of action, preclinical data, pharmacokinetics, clinical efficacy, indications, and contraindications of resmetirom in the management of patients with MASH.

The approval of resmetirom for patients with MASH and moderate to advanced hepatic fibrosis is a major advance in the management of MASH. The recent positive results of the ESSENCE trial of semaglutide, if associated with conditional approval, may offer clinicians two options to treat MASH in patients with moderate to advanced fibrosis.

Nitric oxide (NO) is a bioactive gas that is known to control many physiological processes. In human parenchymal cells, the function of iNOS-derived NO is incompletely understood. Here, we used RNA-seq to examine the role of iNOS-derived NO in the control of gene expression in a human lung epithelial cell line treated with inflammatory cytokines. iNOS-derived NO restricted the expression of genes involved in immune signaling, including the immune-related genes CXCL9 and E-selectin that were not previously known to be inhibited by iNOS. We also determined that iNOS-derived NO inhibits the expression of genes needed for cholesterol/fatty acid biosynthesis in response to cytokine stimulation, a process not previously known to be affected by NO. These findings establish the regulation of immune activation and cholesterol/fatty acid biosynthesis as main functions of iNOS in human parenchymal cells.

Obesity during pregnancy increases the risk of obesity, insulin resistance, diabetes, and the development and progression of chronic kidney disease (CKD) in later life in offspring. Impaired renal autophagic process is linked to kidney dysfunction in the setting of increased renal lipid accumulation. The aim of this study was to elucidate the effect of maternal obesity on kidney injury related to impaired renal autophagic process in the offspring.

Maternal obesity model was conducted using female C57BL/6 mice fed with high-fat diet (HFD) for 8 weeks before mating. HFD was consecutively maintained throughout gestation and lactation. Male offspring were selected for investigation after weaning. Metabolic parameters and kidney morphology were performed. Renal insulin signaling, lipid metabolism, lipid accumulation, fibrosis and autophagy were determined.

Male offspring of HFD fed mothers developed obesity with insulin resistance, hyperglycemia, hyperlipidemia and consequently promoted kidney injury. Maternal obesity increased CD36, FAS, SREBP1c and Perilipin-2 while suppressed PPARα and CPT1A. The reduction of AMPK, SIRT1, Beclin-1, LC3B, and LAMP2 and the elevation of mTOR and SQSTM1/P62 were observed. These findings indicated the impairment of autophagy and renal lipid metabolism exaggerating renal lipid accumulation in the offspring of maternal obesity.

This study demonstrated that long-term HFD consumption in mothers promoted obesity with insulin resistance related kidney injury through the impairment of autophagic process and renal lipid metabolism in the offspring. These circumstances accelerated kidney injury and contributed to an increased susceptibility to CKD in male offspring of maternal obesity.

Emerging evidence indicates that transcriptional regulation plays pivotal roles in modulating cellular vulnerability to ferroptosis. However, the intricate mechanisms governing these processes remain poorly understood. In this study, we identify ATOH8, a basic helix-loop-helix (bHLH) transcription factor, as a key player in ferroptosis regulation. ATOH8 is significantly upregulated in tumor cells following treatment with a ferroptosis inducer. Overexpression of ATOH8 increases the susceptibility of tumor cells to ferroptosis, while deletion of ATOH8 promotes ferroptosis evasion. Mechanistically, ATOH8 confers the sensitivity of tumor cells to ferroptosis by suppressing the transcription of stearoyl-CoA desaturase (SCD). Additionally, another bHLH family member, TCF3, is found to functions as a co-factor with ATOH8 by forming a TCF3-ATOH8 transcriptional repressive complex that suppresses SCD transcription. Furthermore, searching for upstream element reveals that EZH2 epigenetically suppresses ATOH8 expression by promoting DNA methylation in the ATOH8 promoter region and increasing the level of H3K27 me3. Importantly, pharmacological inhibition of EZH2 in a combined with a ferroptosis inducer markedly impedes tumor growth both in vitro and in vivo. Collectively, our study elucidates a molecular link between ferroptosis and epigenetic and transcriptional regulation, highlighting the potential of EZH2 and ATOH8 as therapeutic targets for cancer treatment.

Coronaviruses hijack host cell metabolic pathways and resources to support their replication. They induce extensive host endomembrane remodeling to generate viral replication organelles and exploit host membranes for assembly and budding of their enveloped progeny virions. Because of the overall significance of host membranes, we sought to gain insight into the role of host factors involved in lipid metabolism in cells infected with Middle East respiratory syndrome coronavirus (MERS-CoV). We employed a single-cycle infection approach in combination with pharmacological inhibitors, biochemical assays, lipidomics, and light and electron microscopy. Pharmacological inhibition of acetyl-CoA carboxylase (ACC) and fatty acid synthase (FASN), key host factors in de novo fatty acid biosynthesis, led to pronounced inhibition of MERS-CoV particle release. Inhibition of ACC led to a profound metabolic switch in Huh7 cells, altering their lipidomic profile and inducing lipolysis. However, despite the extensive changes induced by the ACC inhibitor, the biogenesis of viral replication organelles remained unaffected. Instead, ACC inhibition appeared to affect the trafficking and post-translational modifications of the MERS-CoV envelope proteins. Electron microscopy revealed an accumulation of nucleocapsids in early budding stages, indicating that MERS-CoV assembly is adversely impacted by ACC inhibition. Notably, inhibition of palmitoylation resulted in similar effects, while supplementation of exogenous palmitic acid reversed the compound's inhibitory effects, possibly reflecting a crucial need for palmitoylation of the MERS-CoV spike and envelope proteins for their role in virus particle assembly.IMPORTANCEMiddle East respiratory syndrome coronavirus (MERS-CoV) is the etiological agent of a zoonotic respiratory disease of limited transmissibility between humans. However, MERS-CoV is still considered a high-priority pathogen and is closely monitored by WHO due to its high lethality rate of around 35% of laboratory-confirmed infections. Like other positive-strand RNA viruses, MERS-CoV relies on the host cell's endomembranes to support various stages of its replication cycle. However, in spite of this general reliance of MERS-CoV replication on host cell lipid metabolism, mechanistic insights are still very limited. In our study, we show that pharmacological inhibition of acetyl-CoA carboxylase (ACC), a key enzyme in the host cell's fatty acid biosynthesis pathway, significantly disrupts MERS-CoV particle assembly without exerting a negative effect on the biogenesis of viral replication organelles. Furthermore, our study highlights the potential of ACC as a target for the development of host-directed antiviral therapeutics against coronaviruses.

Organisms have to adapt to changes in their environment. Cellular adaptation requires sensing, signalling and ultimately the activation of cellular programs. Metabolites are environmental signals that are sensed by proteins, such as metabolic enzymes, protein kinases and nuclear receptors. Recent studies have discovered novel metabolite sensors that function as gene regulatory proteins such as chromatin associated factors or RNA binding proteins. Due to their function in regulating gene expression, metabolite-induced allosteric control of these proteins facilitates a crosstalk between metabolism and gene expression. Here we discuss the direct control of gene regulatory processes by metabolites and recent progresses that expand our abilities to systematically characterize metabolite-protein interaction networks. Obtaining a profound map of such networks is of great interest for aiding metabolic disease treatment and drug target identification.

Cannabidiol (CBD), a major cannabinoid found in Cannabis sativa L., has been used in the treatment of seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex. Recently, concerns have been raised regarding the male reproductive toxicity of CBD in animal models, such as monkeys, rats, and mice. In our previous studies, we reported that CBD inhibited cell proliferation in both primary human Sertoli cells and mouse Sertoli TM4 cells. Transcriptomic analysis revealed that in primary human Sertoli cells CBD disrupted DNA replication, cell cycle, and DNA repair, ultimately causing cellular senescence. In this study, we further investigated the molecular changes induced by CBD in mouse Sertoli TM4 cells using RNA-sequencing analyses and compared the transcriptomic profile with that of primary human Sertoli cells. Our findings demonstrated that, unlike in primary human Sertoli cells, CBD did not induce cellular senescence but caused apoptosis in mouse Sertoli TM4 cells. Through transcriptomic data analysis in mouse Sertoli TM4 cells, immune and cellular stress responses were identified. Moreover, transcriptomic comparisons revealed major differences in molecular changes induced by CBD between mouse Sertoli TM4 and primary human Sertoli cells. This suggests that primary human Sertoli cells and mouse Sertoli cells may respond differently to CBD.

SREBP1 is a transcription factor that influences lipogenesis by regulating key genes associated with lipid biosynthesis, while AMPK, modulates lipid metabolism by regulating acetyl-CoA carboxylase. The exact role of these metabolic regulators in oleaginous microbes remains unclear. This study identified and manipulated the genes encoding SREBP1 (sre1) and α1 subunit of AMPK (ampk-α1) in Mucor circinelloides WJ11. Individual overexpression of sre1 yielded 32.5 % lipids and 21 g/L biomass, while ampk-α1 deletion combined with sre1 overexpression yielded 42.5 % lipids and 25 g/L biomass in mutant strains. This increase correlated with upregulated expression of key lipogenic genes and enzyme activity, enhancing lipid production and biomass. These surges were correlated with the increased mRNA levels of key genes (acl, acc1, acc2, cme1, fas1, g6pdh1, g6pdh2 and 6pgdh2). Enzyme activity analysis further showed that upregulation of ACL, ACC, ME, FAS, G6PDH and 6PGDH might provide more precursors and NADPH for lipid biosynthesis in sre1 overexpressing strains. Conversely, the activities of these genes and enzymes were markedly downregulated in sre1 deleted mutants consistent with lower lipid production and biomass than the control. These findings open new avenues for research by exploring the coordinated role of sre1 and ampk-α1 in lipid metabolism in M. circinelloides.

Background/Objectives: Sterol regulatory element-binding transcription factor 2 (SREBF2) is a key transcription factor involved in regulating cholesterol homeostasis. However, its role in buffalo mammary gland lipid metabolism remains unclear. Methods: To address this, we isolated and characterized the SREBF2 gene from buffalo mammary glands and performed an in-depth analysis of its molecular characteristics, tissue-specific expression, and functional roles in buffalo mammary epithelial cells (BuMECs). Additionally, we investigated the single nucleotide polymorphisms (SNPs) of SREBF2 in both river and swamp buffalo. Results: The coding sequence (CDS) of buffalo SREBF2 is 3327 bp long and encodes a protein of 1108 amino acid residues. Bioinformatics analysis revealed that the molecular characteristics of buffalo SREBF2 were highly similar across Bovidae species, with collinearity being observed among them. An expression profile analysis revealed that SREBF2 is expressed in all 11 tested tissues of buffalo, with its expression level in the mammary gland being higher during lactation than in the dry period. The knockdown of SREBF2 in BuMECs during lactation led to a significant reduction in the expression of genes involved in triglyceride (TAG) and cholesterol synthesis, including PI3K, AKT, mTOR, SREBF1, PPARG, INSIG1, ACACA, SCD, DGAT1, LPL, CD36, HMGCR, and SQLE. This knockdown led to a 23.53% and 94.56% reduction in TAG and cholesterol levels in BuMECs, respectively. In addition, a total of 22 SNPs were identified in both buffalo types, of which four non-synonymous substitutions (c.301G>C, c.304A>T, c.1240G>A, and c.2944G>A) were found exclusively in the SREBF2 CDS of swamp buffalo, and the assessment revealed that these substitutions had no impact on SREBF2 function. Conclusions: These findings emphasize the critical role of SREBF2 in regulating both triglyceride and cholesterol biosynthesis, providing valuable insights into its functions in buffalo mammary glands.

Oxidative stress is a common event involved in cancer pathophysiology, frequently accompanied by unique lipid metabolic reprogramming phenomena. Oxidative stress is caused mainly by an imbalance between the production of reactive oxygen species (ROS) and the antioxidant system in cancer cells. Emerging evidence has reported that oxidative stress regulates the expression and activity of lipid metabolism-related enzymes, leading to the alteration of cellular lipid metabolism; this involves a significant increase in fatty acid synthesis and a shift in the way in which lipids are taken up and utilized. The dysregulation of lipid metabolism provides abundant intermediates to synthesize biological macromolecules for the rapid proliferation of cancer cells; moreover, it contributes to the maintenance of intracellular redox homeostasis by producing a variety of reducing agents. Moreover, lipid derivatives and metabolites play critical roles in signal transduction within cancer cells and in the tumor microenvironment that evades immune destruction and facilitates tumor invasion and metastasis. These findings suggest a close relationship between oxidative stress and lipid metabolism during the malignant progression of cancers. This review focuses on the crosstalk between the redox system and lipid metabolic reprogramming, which provides an in-depth insight into the modulation of ROS on lipid metabolic reprogramming in cancers and discusses potential strategies for targeting lipid metabolism for cancer therapy.

In this review, we summarize the molecular effects of time-restricted eating (TRE) and its possible role in appetite regulation. We also discuss the potential clinical benefits of TRE in obesity.

TRE is an emerging dietary approach consisting in limiting food intake to a specific window of time each day. The rationale behind this strategy is to restore the circadian misalignment, commonly seen in obesity. Preclinical studies have shown that restricting food intake only during the active phase of the day can positively influence several cellular functions including senescence, mitochondrial activity, inflammation, autophagy and nutrients' sensing pathways. Furthermore, TRE may play a role by modulating appetite and satiety hormones, though further research is needed to clarify its exact mechanisms. Clinical trials involving patients with obesity or type 2 diabetes suggest that TRE can be effective for weight loss, but its broader effects on improving other clinical outcomes, such as cardiovascular risk factors, remain less certain. The epidemic proportions of obesity cause urgency to find dietary, pharmacological and surgical interventions that can be effective in the medium and long term. According to its molecular effects, TRE can be an interesting alternative to caloric restriction in the treatment of obesity, but the considerable variability across clinical trials regarding population, intervention, and follow-up duration makes it difficult to reach definitive conclusions.

Loss of pancreatic islet cell mass and function is one of the most important factors in the development of type 2 diabetes mellitus, and hyperglycemia-induced lesions in other organs are also associated with apoptosis or hyperproliferation of the corresponding tissue cells. The Hippo signaling pathway is a key signal in the regulation of cell growth, proliferation and apoptosis, which has been shown to play an important role in the regulation of diabetes mellitus and its complications. Excessive activation of the Hippo signaling pathway under high glucose conditions triggered apoptosis and decreased insulin secretion in pancreatic islet cells, while dysregulation of the Hippo signaling pathway in the cells of other organ tissues led to proliferation or apoptosis and promoted tissue fibrosis, which aggravated the progression of diabetes mellitus and its complications. This article reviews the mechanisms of Hippo signaling, its individual and reciprocal regulation in diabetic pancreatic pathology, and its emerging role in the pathophysiology of diabetic complications. Potential therapeutics for diabetes mellitus that have been shown to target the Hippo signaling pathway are also summarized to provide information for the clinical management of type 2 diabetes mellitus.

Ovarian cancer (OC) remains a lethal gynecological malignancy with an alarming mortality rate, primarily attributed to delayed diagnosis and a lack of effective treatment modalities. Accumulated evidence highlights the pivotal role of reprogrammed lipid metabolism in fueling OC progression, however, the intricate underlying molecular mechanisms are not fully elucidated.

DLAT expression was assessed in OC tissues and cell lines by immunohistochemistry, western blot and qRT-PCR analysis. The effects of DLAT silencing on changes in lipid metabolism, cell viability, migration, and invasion were examined in SKOV3 and OVCAR3 cells using CCK-8, colony formation, Transwell migration and invasion, and wound-healing assays. GSEA analysis was used to examine the relationship between DLAT and lipid metabolism-related enzymes. Rescue experiments in which SREBP1 was overexpressed in DLAT-silenced cells were carried out. Western blot analysis was performed to determine whether the JAK2/STAT5 signaling pathway was involved in DLAT-regulated SREBP1 expression. Commercially available triglyceride and cholesterol detection kits, as well as Nile Red and Oil red O staining were used to measure lipid metabolism. A subcutaneous tumor model was established in BALB/c mice to confirm the role of the DLAT/SREBP1 axis in OC growth and metastasis in vivo.

DLAT expression was significantly upregulated in OC patient tissue and associated with poor prognosis. Silencing DLAT reduced lipid content and impaired OC cell proliferation, migration, and invasion. DLAT upregulated SREBP1 expression via the JAK2/STAT5 signaling pathway, enhancing expression of fatty acid synthesis enzymes and altering lipid metabolism. SREBP1 was essential for DLAT-dependent OC cell growth and metastasis both in vitro and in vivo.

This study uncovers a novel DLAT/JAK2/STAT5/SREBP1 axis that reprograms lipid metabolism in OC, providing insights into metabolic vulnerabilities and potential therapeutic targets for OC treatment.

Chronic kidney disease (CKD) is by far the most prevalent disease in the world and is now a major global public health problem because of the increase in diabetes, hypertension and obesity. Traditional biomarkers of kidney function lack sensitivity and specificity for early detection and monitoring of CKD progression, necessitating more sensitive biomarkers for early diagnostic intervention. Dyslipidemia is a hallmark of CKD. Advancements in mass spectrometry (MS)-based lipidomics platforms have facilitated comprehensive analysis of lipids in biological samples and have revealed changes in the lipidome that are associated with metabolic disorders, which can be used as new biomarkers for kidney diseases. It is also critical for the discovery of new therapeutic targets and drugs. In this article, we focus on lipids in CKD, lipidomics methodologies and their applications in CKD. Additionally, we introduce novel biomarkers identified through lipidomics approaches and natural products derived from lipidomics for the treatment of CKD. We believe that our study makes a significant contribution to literature by demonstrating that natural products can improve CKD from a lipidomic perspective.

Excessive lipogenesis of the skin triggers some dermatological concerns, such as enlarged pores, acne, and blackheads. Although topical drug treatments can offer temporary relief, their prolonged usage may lead to side effects of dryness, irritation, or allergic reactions. Consequently, the development of safer and efficacious ingredients in cosmetics for managing sebum overproduction represents a significant yet challenging endeavor.

Saponins were extracted from tea (Camellia sinensis) seed meal and purified by macroporous resin in order to investigate the impact of tea seed saponins (TSS) on lipid production in human immortalized sebaceous cells. Moreover, we attempted to reveal the underlying mechanism of TSS on the sebosuppression effect in SZ95 sebocytes stimulated by linoleic acid (LA).

The compositions and chemical structures of TSS were determined using UV-vis absorption spectrum, Fourier transform-infrared (FTIR) spectrum, and ultra-high-performance liquid chromatography-mass spectrometry analysis. An in vitro model of cellular lipid accumulation induced by LA was established. Total lipid synthesis in intracellular SZ95 sebocytes was assessed through Nile Red staining, while triglyceride, cholesterol, and fatty acids were quantified by commercially assay kits. Western blot and quantitative real-time polymerase chain reaction were employed to analyze the protein expression levels involved in the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway as well as the downstream protein and mRNA expressions of sterol regulatory element-binding protein-1 (SREBP-1), peroxisome proliferator-activated receptor γ (PPARγ), and fatty acid synthase (FAS). The localizations of SREBP-1 within the cytoplasm or nucleus were characterized using immunofluorescence staining.

Five saponins were identified in the extracted TSS, all of which were oleanic acid-type pentacyclic triterpenes. TSS treatment significantly alleviated LA-induced lipid accumulation in SZ95 sebocytes. In addition, TSS activated the AMPK/mTOR pathway and downregulated the downstream protein and mRNA expression of transcription factors and enzymes, including SREBP-1, PPARγ, and FAS. Moreover, the TSS blocked the nuclear transfer of SREBP-1 from cytoplasm to nucleus.

In human sebocytes, TSS exhibited sebosuppressive effect as revealed by the inhibited production of total lipids as well as triglyceride, cholesterol, and fatty acids. Moreover, the anti-lipogenesis mechanism by TSS involved the activation of the AMPK/mTOR pathway and downregulated downstream transcription factors and enzymes of SREBP-1, PPARγ, and FAS. Additionally, TSS blocked the SREBP-1 nuclear translocation. These results may justify the potent of TSS as a new candidate for modulating lipogenesis in human SZ95 sebocytes.

MiR-30c and fatty acid synthase (fas) both play important roles in physiological processes such as lipid synthesis and fat metabolism. Predictive analysis revealed that fas is a target gene of miR-30c with multiple seed sites. Seed sites are useful to predict miRNA targeting relationships; however, detailed analyses of seed sites in fish genomes remain poorly studied. In this study, the regulatory relationship between miR-30c and fas, number and effect of seed regions, and mechanism by which miR-30c regulates lipid metabolism were evaluated in blunt snout bream (Megalobrama amblycephala). Four miR-30c target sites for fas were identified using various prediction tools. miR-30c mimics were transfected into 293 T cells, and dual-luciferase reporter assays were used to evaluate the roles of different fas target sites. When a single target site was mutated, relative luciferase activity was higher than that in the control group, with different activity levels depending on the mutation site. When multiple target sites were mutated, relative luciferase activity increased significantly as the number of mutation sites increased and was the highest when the four sites were mutated simultaneously. The miR-30c agomir was injected into the abdominal cavity of M. amblycephala at various concentrations for analyses of physiological and biochemical parameters in the liver and blood and the expression of genes related to lipid metabolism in the liver. Total cholesterol, free fatty acid, triglyceride, and low density lipoprotein levels were significantly lower after miR-30c agomir injection comparing to the control (P < 0.05). Additionally, the expression levels of genes related to lipid metabolism were significantly lower after miR-30c agomir injection than in the control (P < 0.05). In summary, this study identified four specific miR-30c target sites in the 3' UTR of fas mRNA; the effects of these sites are cumulative, and the redundancy ensures the accurate regulation of fas during evolution. In addition, miR-30c has a negative regulatory effect on fas and regulates lipid metabolism via various genes related to this process. Therefore, the regulation of miR-30c can effectively ameliorate the side effects of a high-fat diet on liver function in M. amblycephala.

Acetate can promote milk fat synthesis in dairy cow mammary epithelial cells (BMECs). In this study, gene function analysis was used to explore the role of Ras family secretion-related GTP binding protein 1B (SAR1B) in milk fat synthesis of BMECs and its role and molecular mechanism in acetate-promoted milk fat synthesis. We found that the synthesis of lipid droplets and triglycerides was inhibited, and the expression levels of key genes and proteins in milk fat synthesis such as FASN and ACC were decreased in SAR1B knockout, which was reversed by overexpression of SAR1B. Addition of sodium acetate in BMECs can promote the expression of SAR1B, and SAR1B plays an important role in the synthesis of milk fat promoted by sodium acetate. We further investigated the underlying mechanism of SAR1B upregulation by sodium acetate, and found that sodium acetate could affect SAR1B expression through the positive regulation of SAR1B gene promoter activity by C/EBPβ and PPARγ. In conclusion, the results suggest that SAR1B can promote milk fat synthesis in BMECs, while C/EBPβ and PPARγ play important roles in sodium acetate to promote the expression of SAR1B.

Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) is a chronic disease with increasing prevalence and for which non-invasive biomarkers are needed. Environmental endocrine disruptors (EDs) are known to be involved in the onset and progression of MASLD and assays to monitor their impact on the liver are being developed. Extracellular vesicles (EVs) mediate cell communication and their content reflects the pathophysiological state of the cells from which they are released. They can thus serve as biomarkers of the pathological state of the liver and of exposure to EDs. In this review, we present the relationships between DEHP (Di(2-ethylhexyl) phthalate) and MASLD and highlight the potential of EVs as biomarkers of DEHP exposure and the resulting progression of MASLD.

Epithelial ovarian cancer (EOC) has the highest mortality rate among malignant tumors of the female reproductive system and the lowest survival rate. This poor prognosis is due to the aggressive nature of EOC, its late-stage diagnosis, and the tumor's ability to adapt to stressors through metabolic reprogramming. EOC cells sustain their rapid proliferation by altering the uptake, utilization, and regulation of carbohydrates, lipids, and amino acids. These metabolic changes support tumor growth and contribute to metastasis, chemotherapy resistance, and immune evasion. Targeting these metabolic vulnerabilities has shown promise in preclinical studies, with some therapies advancing to clinical trials. However, challenges remain due to tumor heterogeneity, adaptive resistance mechanisms, and the influence of the tumor microenvironment. This review provides a comprehensive summary of metabolic targets for EOC treatment and offers an overview of the current landscape of clinical trials focusing on ovarian cancer metabolism. Future efforts should prioritize combination therapies that integrate metabolic inhibitors with immunotherapies or chemotherapy. Advances in precision medicine and multi-omics approaches will be crucial for identifying patient-specific metabolic dependencies and improving outcomes. By addressing these challenges, metabolism-based therapies can significantly transform the treatment of this devastating disease.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) was first reported in 2003 and confirmed to be strongly associated with familial hypercholesterolemia. Small-molecule inhibitors targeting PCSK9 provide an effective and safe method for managing hypercholesterolemia and reducing the cardiovascular risk. In recent years, increasing evidence has indicated other important roles for PCSK9 in inflammation, tumors, and even immune regulation. PCSK9 might be an attractive regulator of T-cell activation and expansion. It might mediate inflammation and regulate other types of immune cells. In this review, we summarize the current advances in the field of PCSK9 and provide a narrative of the biological processes associated with PCSK9. The relationships between PCSK9 and different T cells were investigated in depth. Finally, the signaling pathways associated with PCSK9 and the immune response are also summarized in this review.

The diagnosis of low-grade fibroblastic/myofibroblastic tumors of acral sites can be challenging. These tumors encompass a diverse group of neoplasms with a spectrum of biologic potential ranges from benign to overtly malignant. They often demonstrate significant clinical, radiologic, and immunophenotypic overlap, in which the molecular phenotype may play an important diagnostic role to arrive at the final diagnosis. Herein, we report a case of soft tissue mass lesion presented on the palm of an adult patient for four months. Histologically, the tumor consisted of primarily low-grade spindle cells expressing smooth muscle actin. Molecular testing revealed a novel SREBF1::USP6 fusion gene, confirming the final diagnosis of nodular fasciitis and ultimately expanding its molecular profile. This case highlights the diagnostic value of single, cost-effective, targeted molecular panel to arrive at an accurate diagnosis and provide helpful therapeutic information.

Glycerol kinase (GK) participates in triglyceride (TG) synthesis by catalyzing glycerol metabolism. Whether GK contributes to nonalcoholic fatty liver (NAFL) is unclear. The expression of hepatic Gk is found to be increased in diet-induced and genetic mouse models of NAFL and is positively associated with hepatic SREBP-1c expression and TG levels. Cholesterol and fatty acids stimulate GK expression in hepatocytes. In HFD-induced NAFL mice, knockdown of hepatic Gk decreases expression of SREBP-1c and its target lipogenic genes as well as DGAT1/2, increases serum glycerol levels, decreases serum TG levels, and attenuates hepatic TG accumulation. Overexpression of GK in hepatocytes in mice or in culture produces opposite results. Mechanistic studies reveal that GK stimulates SREBP-1c transcription directly by binding to its gene promoter and indirectly by binding to SREBP-1c protein, thereby increasing lipogenic gene expression and de novo lipogenesis. Studies with truncated GK and mutant GKs indicate that GK induces SREBP-1c transcription independently of its enzyme activity. GK contributes to lipid homeostasis under physiological conditions by catalyzing glycerol metabolism rather than by regulating SREBP-1c transcription. Collectively, these results demonstrate that increased hepatic GK promotes de novo lipogenesis and TG synthesis in NAFL by stimulating SREBP-1c transcription and DGAT1/2 expression and catalyzing glycerol metabolism.

The development of cancer is accompanied by metabolic reprogramming, and the liver serves as a central hub for lipid transportation. Apigenin, a plant-derived flavonoid, demonstrates potent anticancer properties across various cancer types and exhibits promising potential as a therapeutic agent for cancer treatment. However, there are limited studies focusing on the downstream targets of apigenin. Moreover, there are few reports on the impact of apigenin in lipid metabolism within liver cancer cells.

The objective is to elucidate the metabolic mechanism underlying the inhibitory effect of apigenin on liver cancer progression, search for downstream targets and provide reliable data support for the clinical trials of apigenin.

Anticancer effects of apigenin were detected at cellular and molecular levels in vitro, and downstream targets of apigenin, especially metabolic pathway genes, were analyzed by transcriptome. Next, the downstream target of apigenin was verified and the biological function of the downstream target was examined. Finally, the downstream target of apigenin was further verified by restoring target gene expression.

Cellular molecular experiments showed that Apigenin inhibited the proliferation, migration, invasion and lipid metabolism of hepatocellular carcinoma (HCC) cells. Transcriptome analysis showed apigenin widely regulates histone demethylase, particularly histone H3K4 lysine demethylase 1A (KDM1A). Apigenin treatment inhibited the expression of KDM1A protein and mRNA levels in liver cancer cells, molecular docking predicted the interaction between apigenin and KDM1A. Furthermore, downregulation KDM1A inhibited the proliferation and lipid metabolism of HCC cells, in the same way, overexpressing KDM1A promoted proliferation of HCC cells. Finally, restoring KDM1A expression partially attenuated the effects of apigenin on lipid metabolism in HCC cells.

In conclusion, our study provides compelling evidence that apigenin inhibits liver cancer progression and elucidates its mechanism of action in regulating lipid metabolism. Specifically, we find that apigenin suppresses the progression of HCC cells by downregulating genes involved in lipid metabolism. Additionally, our results indicate that KDM1A acts as a downstream target of apigenin in the inhibition of lipid metabolism in HCC. These findings offer experimental support for the potential use of apigenin as a therapeutic agent for liver cancer, highlighting its relevance in future clinical applications.

The prognosis of HER2-positive breast cancer (BC) has improved with the development of anti-HER2 therapies; however, the problem remains that there are still cases where anti-HER2 therapies do not respond well. We found that the expression of SREBF2, a master transcriptional factor in the mevalonate pathway, was correlated with ERBB2 (HER2) expression and a poor prognosis in HER2-positive BC. The target gene expressions of SREBF2 were associated with higher expression of ERBB2 in HER2-positive BC cells. Statins, anti-hypercholesterolemia drugs that inhibit the mevalonate pathway, enhanced the efficacy of HER2-targeting agents with inducing apoptosis in a geranylgeranylation-dependent manner. Mechanistically, statins specifically inhibited membrane localization of Rac1, a target protein of geranylgeranylation, and suppressed the activation of HER2 downstreams AKT and ERK pathways. Consistently, retrospective analysis showed a longer recurrence-free survival in Rac1-high/HER2-positive BC patients treated with HER2-targeting agents with statins than without statins. Our findings thus suggest that Rac1 expression could be used as a biomarker to stratify HER2-positive BC patients that could benefit from dual blockade, i.e., targeting HER2 with inhibition of geranylgeranylation of Rac1 using statins, thereby opening avenues for precision medicine in a new subset of Rac1-high/HER2-positive BC.