Sequelae of pelvic inflammatory disease (SPID) is a common gynecological disease, which is often accompanied by pathological changes and inflammation, and may even lead to infertility. The Yi-Qi-Qing-Shi-Hua-Yu method (YQQSHY), as a traditional Chinese medicine treatment method, is considered to have potential therapeutic effects on SPID. This study will explore the efficacy and potential mechanism of YQQSHY on SPID. This study established a SPID rat model by mixed bacteria and evaluated the regulatory effect of YQQSHY on uterine tissue pathology, immune status, and intestinal flora in SPID rats through histopathology, molecular experiments, immunology, and intestinal flora sequencing analysis. H&E staining showed that YQQSHY significantly reduced the pathological changes and fibrosis in the uterine tissue of SPID rats. ELISA results showed that YQQSHY could significantly reduce the levels of pro-inflammatory cytokines in the serum and vaginal secretions of SPID rats and increase the expression of anti-inflammatory factors. Flow cytometry analysis showed that the YQQSHY treatment group significantly adjusted the proportion of T cells in the peripheral blood of SPID rats. Western blot showed that YQQSHY can regulate TLR4, MyD88, p-NF-KB p65, and induce the transcription of p65 into the nucleus. Immunofluorescence examination of T cell subsets in uterine tissue. In addition, intestinal flora sequencing results showed that YQQSHY significantly modulated the composition and diversity of the intestinal flora of SPID rats. In conclusion, YQQSHY inhibits inflammatory response, regulates T cell ratio, and improves intestinal flora structure through the TLR4/NF-κB signaling pathway, which is the main mechanism for improving uterine inflammation and fibrosis in SPID rats. These findings provide experimental basis and theoretical support for further exploring the application of YQQSHY in clinical treatment.

Pulmonary fibrosis (PF) is always exacerbated by the comorbidity of lung adenocarcinoma (LUAD), and patients frequently died from the complications of PF instead of lung cancer. Although many studies have unveiled the mechanisms underlying PF exacerbation due to lung cancer resection and radiotherapy, the influence of lung cancer itself on PF remains enigmatic.

We cocultivated mouse pulmonary cells with mouse LUAD cells to explore the influence of LUAD on the pathogenesis and progression of PF. Additionally, a comorbidity model of PF with LUAD was established in mice via intratracheal injection of bleomycin (BLM) followed by in situ transplantation of LUAD cells. Furthermore, immunofluorescence, immunohistochemistry, and molecular analyses were employed to elucidate the mechanisms underlying the exacerbation of PF by the comorbidity of LUAD.

We found that PF was significantly exacerbated by LUAD. In the microenvironment of LUAD, the epithelial-mesenchymal transition (EMT) was predominantly activated in lung epithelial cells, while the transformation of lung fibroblasts into myofibroblasts was markedly induced. The TGF-β and GSK-3β pathways were differentially activated in lung epithelial cells and fibroblasts. Furthermore, clinical samples confirmed the involvement of these pathways in the process of PF exacerbation induced by LUAD in patients' lung lesions of PF with LUAD.

This study initially reveals that LUAD exacerbates PF by modulating epithelial cells and fibroblasts through TGF-β and GSK-3β pathways differentially. Practically, targeting the pathways of TGF-β and GSK-3β may promise a potential strategy for the prophylaxis of PF exacerbation in patients with LUAD.

Inspired by the intriguing structures and significant activities of Ganoderma triterpenoids (GTs), the EtOAc extract of Ganoderma applanatum was phytochemically investigated, leading to the isolation of 11 GTs, including 10 new one (1-10). Their structures including absolute configurations, were elucidated through IR, UV, HRESIMS, 1D NMR and 2D NMR data analyses. Notably, applanoids J (1) and K (2) represent the first example of GTs with an unprecedented B-seco-lanostane architecture featuring 1,4-cyclohexanedione motif. Meanwhile, compounds 1-7 and 9-11 were evaluated for their hepatoprotective activity using TGF-β1-induced liver fibrosis model, and some of them such as compounds 2, 4, 6, 7 and 10 significantly suppressed the abnormal upregulation of fibrosis-related genes FN, ACTA2 (encode α-SMA) and COL1A1. Mechanistic studies suggested that the anti-liver fibrosis effect of compound 7 may be mediated through inhibition of the TGF-β/Smad signaling pathway. This study not only illustrates the structural diversity of GTs but also highlights their potential as promising anti-liver fibrosis agents.

Hepatic fibrosis (HF) is a critical marker of advanced‑stage chronic liver disease and involves pivotal contributions from hepatic stellate cells (HSCs). Currently, there are no effective treatments for HF. Umbelliferone (7‑hydroxycoumarin; UMB) is a natural compound with significant anti‑inflammatory, antioxidant and anti‑tumor activities. However, its potential efficacy in treating HF has not been studied. The present study explored the protective effects of UMB against HF, targeting the TGF‑β1‑Smad signaling pathway to explore the underlying mechanisms of UMB. Carbon tetrachloride (CCl4) was injected intraperitoneally to induce HF in rats and primary HSCs were treated in vitro with UMB to investigate the improvement effect of UMB on HF. The levels of fibrosis markers, inflammation, oxidative stress and TGF‑β1‑Smad signaling pathway in the rat liver tissue and HSCs were detected using hematoxylin and eosin staining, enzyme‑linked immunosorbent assay, reverse transcription‑quantitative PCR, Cell Counting Kit‑8 and western blotting. The improvement in liver histopathology, liver function indexes and fibrosis markers demonstrated that UMB markedly inhibited the CCl4‑induced HF and inflammation in the rats. Additionally, UMB prominently reduced the pro‑inflammatory factors and oxidative stress levels. In vitro, UMB markedly inhibited primary HSC activation and decreased alpha‑smooth muscle actin and collagen I expression. The mechanism experiment proved that UMB inhibited the TGF‑β1‑Smad signaling pathway and ameliorated HF. The present study was the first to demonstrate, to the best of the authors' knowledge, that UMB might be a promising natural active compound for treating HF. Its therapeutic effect is associated with its modulation of the TGF‑β1‑Smad signaling pathway.

Sodium dehydroacetate (Na-DHA), a synthetic preservative under tightened regulations, was evaluated for multi-organ toxicity using network toxicology. ADMETlab3.0 predicted genotoxicity, hepatotoxicity, and carcinogenicity risks. Target mining identified 13 cancer-related, 11 liver injury-related, and 8 genotoxicity-related core genes, with shared hubs (ALOX5, PTGS2, SMAD3, TNF) across pathologies. Functional analyses revealed inflammation, oxidative stress, and immune dysregulation as central mechanisms. KEGG pathway analysis linked cancer/liver injury to AGE-RAGE signaling (TNF, NOX4) and genotoxicity to efferocytosis impairment (PTGS2, ALOX5), suggesting DNA repair disruption. The integrated network demonstrated Na-DHA's pleiotropic effects through convergent pathways, transcending organ-specific toxicity. This systemic profile challenges conventional single-endpoint assessments, advocating comprehensive multi-organ risk evaluation.

Sarcopenia is a prevalent age-related disorder characterized by progressive loss of muscle mass, strength, and physical performance. While genome-wide association studies (GWAS) have explored isolated traits, the multifactorial genetic architecture underlying sarcopenia remains poorly defined. In this study, we constructed a comprehensive genetic factor to explain the genetic architecture of sarcopenia, and explore causal associations, genetic comorbidities, and mediating pathways linking sarcopenia to 30 urological diseases.

Based on the European Working Group on Sarcopenia in Older People (EWGSOP) criteria, six sarcopenia-related phenotypes were selected. A multivariate GWAS framework using genomic structural equation modeling (genomic SEM) was constructed, with an effective sample size of 651,820 individuals. Bidirectional Mendelian randomization (MR) was employed to assess causal relationships between sarcopenia and 30 urological diseases. Genetic correlation, tissue-specific heritability enrichment, shared risk genes, and gene set enrichment analyses were conducted to dissect genetic comorbidities between sarcopenia and urological diseases. Multi-omic mediation analysis was conducted to identify potential pathways mediated by blood proteins, metabolites, and immune traits.

Multivariate GWAS identified 215 loci and 30,869 single-nucleotide polymorphisms (SNPs) associated with polygenic architecture of sarcopenia. Bidirectional Mendelian randomization revealed causal links between sarcopenia and urological diseases, notably hyperplasia of prostate (BPH; OR = 1.17, P = 0.043) and acute tubulointerstitial nephritis (ATIN; OR = 1.14, P = 0.028). Genetic comorbidity analyses identified local genetic correlations between sarcopenia and BPH, and highlighted tissue-specific heritability enrichment in Cells Cultured fibroblasts tissue for both traits, while no genetic correlation was found with ATIN. We identified 75 shared risk genes for sarcopenia and BPH, which were enriched in cellular component biogenesis, RNA binding, and metabolic pathways. Multi-omic mediation analyses prioritized 17 metabolites and proteins linking sarcopenia to BPH and ATIN, though no significant immune mediators were identified.

These findings unveil a shared genetic architecture between sarcopenia and urological diseases, especially BPH, with heritability enrichment in fibroblast tissue and metabolic dysfunction emerging as the significant overlapping pathway.

Kinase suppressor of Ras 1 (KSR1) serves as a scaffold protein within the RAS-RAF pathway and plays a role in tumorigenesis, immune regulation, cell proliferation, and apoptosis. However, the specific role of KSR1 in the formation and progression of fibrotic diseases, such as intrauterine adhesions (IUA), remains unclear. This study aims to investigate KSR1 expression in IUA and the mechanisms underlying its role in promoting IUA progression. KSR1 was found to be significantly overexpressed in the endometrium of both IUA model rats and patients with IUA. KSR1 is positively involved in the regulation of proliferation, migration, and fibrosis (FN1, Collagen I, α-SMA) in immortalized human endometrial stromal cells (THESCs). Furthermore, KSR1 knockdown was observed to inhibit the fibrosis, proliferation, and migration of transforming growth factor-β1 (TGF-β1)-induced THESCs. Further studies demonstrated that the key proteins of the MEK/ERK signaling pathway, p-MEK1 and p-ERK1/2, were significantly overexpressed in the uterus of IUA rats. In vitro rescue experiments confirmed that the MEK/ERK pathway inhibitor U0126 (An ERK inhibitor) effectively suppressed the enhanced fibrosis, proliferation, and migration induced by KSR1 overexpression. In conclusion, this study demonstrates that KSR1 promotes IUA by enhancing proliferation, migration, and fibrosis of endometrial stromal cells via the MEK/ERK signaling pathway.

Damage to myocardial tissues, leading to myocardial fibrosis, is a significant pathological hallmark across various heart diseases. SMAD3, a central transcriptional regulator within the transforming growth factor-beta (TGF-β) signaling pathway, plays a pivotal role in the pathological progression of myocardial fibrosis and cardiac remodeling. It intricately regulates physiological and pathological processes encompassing cell proliferation, differentiation, tissue repair, and fibrosis. Notably, SMAD3 exerts crucial influences in myocardial fibrosis subsequent to myocardial infarction, pressure overload-induced myocardial fibrosis, diabetic cardiomyopathy (DCM), aging-associated cardiac fibrosis and myocarditis-related myocardial fibrosis. The targeted modulation of genes or the utilization of compounds, including traditional Chinese medicine (paeoniflorin, baicalin, and genistein et al.) and other pharmaceutical agents that modulate SMAD3, may offer avenues for restraining the pathological cascade of myocardial fibrosis. Consequently, targeted regulation of SMAD3 associated with myocardial fibrosis may herald novel therapeutic paradigms for ameliorating myocardial diseases.

About 2 to 3 % of all new cancer cases worldwide are renal carcinomas. Nevertheless, during the past few decades, there has been a 2 % annual increase in the prevalence of this malignancy worldwide. Within three years, 20 to 40 % of individuals with early-stage malignancies may either have a local recurrence or metastasis, and 20 to 30 % will receive a diagnosis of metastatic illness. For renal cancer, traditional chemotherapy and radiation are ineffective, while metastatic-focused treatments are linked to several side effects and the quick emergence of resistance. As a silent disease with no specific and identifiable signs and symptoms and an aggressive nature, there is an urgent need to discover trustworthy prognostic biomarkers as well as novel therapeutic targets. With multiple studies suggesting that renal carcinoma is a disease with complex genomic and epigenomic backgrounds influencing tumor development and progression, it is essential to study the dysregulated cellular pathways behind this disease to address this need. In this context, the canonical TGF-β signaling pathway could reveal interesting clues. The current study attempts to outline the role of this signaling mechanism in renal cancer dynamics, with a focus on its potential prognostic, predictive, and therapeutic relevance.

This study investigated the involvement of TGF-β signaling pathway-associated genes in the pathogenesis of Fuchs endothelial corneal dystrophy (FECD). The RNA-sequencing analysis of corneal endothelial cells (CECs) from FECD patients revealed significant alterations in multiple TGF-β superfamily genes, with 9 genes upregulated (including BMP6, GDF5, and TGF-β2) and 10 genes downregulated (including BMP2, NOG, and INHBA) compared to controls. Quantitative PCR validation confirmed the elevated expression of GDF5 (3.35-fold in non-expanded and 7.66-fold in expanded TCF4), TGF-β2 (6.17-fold and 11.5-fold), and TGF-β1 (1.78-fold and 1.58-fold) in FECD patients with and without TCF4 trinucleotide repeat expansion. Ex-vivo experiments using donor corneas demonstrated that TGF-β2 stimulation significantly increased the expression of extracellular matrix (ECM) components associated with guttae formation, including fibronectin, types I and VI collagens, and other matrix proteins. Immunofluorescence confirmed increased fibronectin protein expression in the corneal endothelium following TGF-β1 or TGF-β2 treatment. This study provides the first comprehensive analysis of TGF-β superfamily involvement in FECD and suggests that GDF5, found to be upregulated in FECD, may contribute to the disease process. These findings further indicate that dysregulation of TGF-β signaling pathways drives the characteristic ECM accumulation in FECD, potentially offering new therapeutic targets for this progressive corneal disease involving fibrosis-related alterations. Future research is warranted to clarify GDF5's specific role and mechanistic impact on FECD pathogenesis.

Nintedanib is a potent antifibrotic angiokinase inhibitor approved for various fibrotic lung diseases. Potential therapeutic efficacy of nintedanib in various inflammatory diseases is under investigation. In this study, we investigated the therapeutic effect of nintedanib on adipogenesis and fibrosis in orbital fibroblasts in patients with Graves' orbitopathy (GO).

Primary orbital fibroblasts were cultured from orbital connective tissue of patients with GO and healthy controls. The cells were pretreated with nintedanib before stimulation with either interleukin (IL)-1β, transforming growth factor (TGF)-β, insulin-like growth factor-1, or IL-11. Fibrosis-related and intracellular signaling protein expressions were assessed using western blotting. Hyaluronan and procollagen concentrations were quantified using enzyme-linked immunosorbent assay. Adipogenesis was quantified by Oil Red O staining and the levels of adipogenic transcription factors were determined by Western blot.

TGF-β-induced fibronectin and collagen 1/3 protein expression was abrogated by nintedanib treatment. Nintedanib decreased the phosphorylation of signal transducer and activator of transcription 3, SMAD 2/3, Akt, c-Jun N-terminal kinase, and extracellular regulated protein kinase. Exposure to nintedanib hindered adipocyte differentiation and expression of adipogenic transcription factors, including peroxisome proliferator-activated receptor γ, CCAAT/enhancer-binding protein α/β, adipocyte protein 2, adiponectin, and leptin. Additionally, nintedanib reduced hyaluronan and procollagen secretion.

Nintedanib suppressed profibrotic protein production, adipogenesis, and hyaluronan production in in vitro. These findings indicate the potential therapeutic efficacy of nintedanib in GO management.

Oral submucosal fibrosis is a highly malignant oral condition that necessitates the use of sophisticated therapeutic procedures. OSF is a multifactorial precancerous condition induced by areca nut chewing, deficiencies in vitamins and trace minerals, immunological aspects, and hereditary factors. Adipose tissue-derived mesenchymal stem cells possess the capability for multidirectional activation and are extensively distributed throughout the body. They have minimal immunogenicity and are extensively utilized in cancer treatment. Exosomes are extracellular vesicles produced by the intracellular route. They are biological carriers comprising microRNA, messenger RNA, lipids and proteins crucial for intercellular communication. ADSC exosomes, serving as a vehicle for miRNA, possess accessibility and little immunogenicity. They can significantly contribute to adipose tissue regrowth, angiogenesis, immunological modulation, and tissue repair. ADSC-Exo exhibits antifibrotic properties and may serve as a potential treatment for OSF. This review presents a novel therapeutic approach and clarifies the precise mechanisms involved in the clinical management of OSF using ADSC-Exo.

Withania coagulans encompasses many active phytoconstituents, which have been used to treat many ailments. Prior research has shown that fruit extract of Withania coagulans has anti-inflammatory properties and effectively reduces oxidative stress in various diseases. Nevertheless, its effects are not obscured in the silica (SiO2) induced pulmonary fibrosis (PF). In the current study, an ethanolic fruit extract of Withania coagulans (WCE) was prepared, and its effects and underlying mechanisms on SiO2-induced PF in rats were elucidated. LC-MS/MS analysis identified various bioactive phytoconstituents, secondary plant metabolites, and flavonoids in the WCE. In vitro, results showed that the WCE exhibited no toxicity towards A549 cells, reduced the production of reactive oxygen species, and inhibited cell migration. Further, WCE abrogated alveolar wall thickening, reduced inflammatory cell infiltration, and maintained lung architecture. It also suppresses collagen accumulation and mucus production, abrogating inflammation by downregulating nuclear factor kappa B (NF-κB-p65)/ NOD-like receptor protein 3 (NLRP3) and cytokine levels. It suppresses oxidative and endoplasmic reticulum stress induced by SiO2 by downregulating thioredoxin-interacting protein (TXNIP), activating transcription factor 6 (ATF6), and C/EBP Homologous Protein (CHOP) proteins. Additionally, WCE, by suppressing EMT and transforming growth factor beta 1 (TGF-β1)/Suppressor of Mothers against Decapentaplegic (Smad) pathway, mitigated PF in rats. Taken together, WCE via anti-inflammatory and anti-oxidative properties inhibited SiO2-induced PF, and therefore, it can be envisaged as an effective antifibrotic agent to treat PF.

Fibrosis, the excessive production and disorganised deposition of extracellular matrix proteins, can occur in any organ system, disrupting functionality and causing fatality. The number, efficacy and safety of antifibrotic drugs are incredibly limited. Therapeutics which elevate intracellular cyclic adenosine monophosphate (cAMP) offer a potential solution. In this review, we present the signalling mechanisms involved in fibrosis pathophysiology, how cAMP and its effectors might interact with these pathways, and the current preclinical and clinical efforts in this field. cAMP elevating agents have the potential to be future antifibrotic drug candidates, but further studies are required, particularly to develop tissue specific therapeutics.

Age-related macular degeneration (AMD), the leading cause of irreversible blindness worldwide, represents a complex neurodegenerative disorder whose pathogenesis remains elusive. At the core of AMD pathophysiology lies the retinal pigment epithelium (RPE), whose epithelial-mesenchymal transition (EMT) has emerged as a critical pathological mechanism driving disease progression. This transformative process, characterized by RPE cell dedifferentiation and subsequent extracellular matrix remodeling, is orchestrated through a sophisticated network of molecular interactions and cellular signaling cascades. Our review provides a comprehensive analysis of the molecular landscape underlying RPE EMT in AMD, with particular emphasis on seven interconnected pathological axes: (i) oxidative stress and mitochondrial dysfunction, (ii) hypoxia-inducible factor signaling, (iii) autophagic flux dysregulation, (iv) chronic inflammatory responses, (v) complement system overactivation, (vi) epigenetic regulation through microRNA networks, and (vii) key developmental signaling pathway reactivation. Furthermore, we evaluate emerging therapeutic strategies targeting EMT modulation, providing a comprehensive perspective on potential interventions to halt AMD progression. By integrating current mechanistic insights with therapeutic prospects, this review aims to bridge the gap between fundamental research and clinical translation in AMD management.

Inflammation plays a key role in abdominal aortic aneurysm (AAA), with macrophages being crucial. Growth differentiation factor 15 (GDF15) is a new anti-inflammatory cytokine potentially useful in AAA diagnosis and treatment, but its role is unclear.

In mice with AAA, GDF15 expression was higher in lesioned tissues. Daily intraperitoneal injection of recombinant GDF15 (rGDF15) reduced aortic dilation, inflammation, degradation of aortic wall elastin and collagen, cellular apoptosis, and increased smooth muscle cells. GDF15 knockdown worsened AAA severity. Immunohistochemistry and immunofluorescence showed rGDF15 treatment reduced M1 macrophage polarization and enhanced M2 polarization, decreasing the M1/M2 ratio. GDF15 knockdown had the opposite effect. Additionally, Amphiregulin (AREG) expression increased with rGDF15 treatment and decreased with GDF15 knockdown. Immunofluorescence colocalization revealed lower AREG expression in M1 macrophages and higher AREG expression in M2 macrophages, suggesting that AREG may be involved in the regulation of macrophage polarization by GDF15 in AAA. Mechanistically, GDF15 upregulates AREG expression by activating the TGF-βR/SMAD2/3 signaling pathway, thereby inhibiting M1 polarization and promoting M2 polarization of macrophages.

This study demonstrates that exogenous injection of rGDF15 upregulates AREG expression and regulates macrophage polarization, thereby inhibiting AAA. GDF15 may not only serve as a diagnostic and prognostic marker for AAA but also as a potential molecular target for therapeutic intervention in AAA.

The "Developmental Origins of Health and Disease" (DOHaD) theory suggests that prenatal exposure to harmful environmental factors may impair fetal tissue development, increasing the risk of diseases later in life. This study investigated the effects of prenatal exposure to polystyrene microplastics (PS-MPs) on offspring lung development. Pregnant Sprague-Dawley rats were randomly assigned to receive PS-MPs in drinking water until delivery, with a control group receiving standard water. Offspring were assessed at 7 and 120 d after birth without further PS-MPs exposure. Histopathological examination at 7 d revealed PS-MPs deposits, alveolar collapse, and inflammation in lung tissue. Gene expression analysis showed disruptions in tight junctions, transcriptional regulation, and transforming growth factor-beta (TGF-β) pathways. By day 120, lung dysfunction and structural changes, consistent with emphysema were observed. These findings demonstrate that prenatal PS-MPs exposure adversely affects lung development potentially increasing the risk of respiratory diseases. Public health measures should address the potential hazards of microplastics to fetal health.

Idiopathic pulmonary fibrosis (IPF) is a long-term, diffuse pulmonary parenchyma lesion that primarily affects middle-aged and older adults. It is characterized by pulmonary interstitial fibrosis of unknown cause. The death rate upon diagnosis is higher than that of many other cancer types. Mesenchymal stem cell (MSC) treatment of organ fibrosis is a hot topic in preclinical and clinical research because it effectively treats IPF. In recent years, decorin (DCN) has been regarded as a critical mediator for its anti-inflammatory and antifibrotic effects. The purpose of this study was to generate human umbilical cord MSCs (HUC-MSCs) that overexpress DCN and to investigate the safety, mechanism, and effectiveness of using these cells to cure pulmonary fibrosis caused by bleomycin (BLM). First, lentiviral (LV) particles carrying the therapeutic DCN gene (LV-DCN) and control LV particles were created and transfected using the plasmid vector GV208 to create a viral solution for infecting HUC-MSCs. These solutions were used to create a DCN overexpression cell line and an MSC-Con. cell line infected with the control lentivirus. Intratracheal injection of BLM was used to establish a rat model of pulmonary fibrosis. On the second day following modeling, different treatments were administered, and the body weight and survival status of the rats were noted. The relevant tests were performed on days 15 and 29 following modeling. The results demonstrated that the overexpression of DCN did not affect the properties of HUC-MSCs and that these cells were effective in treating IPF. MSC-Con. and MSC-DCN reduced systemic inflammation by reducing serum interleukin (IL) 1β. Both cell types successfully treated pulmonary fibrosis in rats, as demonstrated by hematoxylin and eosin (HE) and Masson staining. MSC-DCN showed better efficacy due to lower mortality, higher weight gain, less alveolar inflammation, and less fibrosis. The safety of venous transplantation with MSCs was established by HE staining of the heart, liver, spleen, and kidney, as well as serum lactate dehydrogenase (LDH), creatinine (CRE), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels. Immunohistochemical (IHC) staining of CD68 and CD206 in lung tissue and in vitro experiments on THP-1-induced M2 macrophage polarization and transforming growth factor-beta 1 (TGF-β1)-induced MRC-5 fibrosis indicated that MSC-DCN may mitigate lung inflammation by altering macrophage recruitment and polarization and inhibiting TGF-β1 expression to reduce fibrous hyperplasia and collagen deposition, thereby improving the treatment of BLM-induced IPF.

Pulmonary fibrosis (PF) is a disease characterized by dysregulated extracellular matrix deposition and aberrant fibroblast activation. Emerging evidence implicates that dysregulated copper metabolism contributed to fibrotic pathogenesis, yet its role and the therapeutic potential of copper modulation remain underexplored. This study investigated the involvement of cuproptosis, a programmed cell death induced by intracellular copper overload, in PF and evaluated the therapeutic efficacy of the copper chelator tetrathiomolybdate (TTM). In a bleomycin (BLM)-induced murine PF model, intratracheal BLM administration elevated lung copper levels, upregulated oligomerized DLAT, and exacerbated fibrosis, as evidenced by collagen deposition, α-smooth muscle actin, and transforming growth factor-beta expression. TTM treatment significantly attenuated fibrotic progression, reduced oxidative stress, and suppressed Olig-DLAT accumulation. In vitro, copper ionophores induced cuproptosis in bronchial epithelial cells, characterized by reduced viability, elevated intracellular Cu⁺, and Olig-DLAT aggregation, which were reversed by TTM. Furthermore, TTM mitigated TGF-β-driven epithelial-mesenchymal transition (EMT) and fibroblast-to-myofibroblast transition (FMT), downregulating collagen-1 and restoring E-cadherin expression. These findings establish cuproptosis as a novel mechanistic contributor to PF and highlight TTM's dual role in restoring copper homeostasis and inhibiting fibrogenic pathways, offering a promising therapeutic strategy for fibrotic lung diseases.

Ureteral stricture is a difficult urological problem with no optimal solution and is the result of scar hyperplasia and fibrosis caused by ureteral injury. Preventing the formation of ureteral strictures around drug-loaded ureteral stents is at the heart of the current research. TGF-β1 is a key factor affecting collagen deposition and fiber formation. Therefore, in this study, we established a rabbit ureteral stricture model, implanted a ureteral stent loaded with TGF-β1-siRNA for treatment, and compared the histopathology of ureteral stricture and the protein expression of genes related to the formation of stricture between different groups to test their therapeutic effects. We used sustained- and slow-release properties of the nanoparticles that were confirmed through in vitro experiments. The results of the fluorescence immunoassay showed that siRNA loaded by ureteral stents had high transfection efficiency on human ureter epithelial cells in vivo. In addition, the rabbit ureteral stricture model experiment verified that TGF-β1-siRNA could effectively transfect into ureteral tissues and inhibit the expression of TGF-β1, thereby inhibiting ureteral stricture. At the same time, the images of rabbit gross anatomy specimens showed that the hydronephrosis could also be effectively relieved. In summary, all the results mentioned above suggest that ureteral stents combined with RNA interference technology and a nanoparticle delivery system have broad prospects for clinical application in the suppression of ureteral stricture.

The objective of this study was to assess the potential of TCF7L2, CCAT2, and PVT1 LncRNAs, c-Myc, and miR-33 as biomarkers for early diagnosis and differentiation of oral squamous cell carcinoma (OSCC) and premalignant lesions.

Bioinformatics tools, including COSMIC, GeneMANIA, PathVisio, KEGG Pathway Database, IntOGen, and WikiPathways, were used to investigate the signaling pathways of cancer-associated genes. The limma package was utilized for statistical analysis to identify Differentially Expressed Genes (DEGs) between OSCC tumor and normal samples. The regulatory microRNAs were analyzed using miRDB, miRWalk, and TargetScan. The type of cancer for analysis was selected using IntOGen. The expression levels of LncRNAs, miR-33, and c-Myc were measured by polymerase chain reaction (PCR) in 28 OLP and 30 OSCC tissue samples, compared to 30 healthy and 30 OSCC-adjacent tissue specimens as control groups. Data were analyzed using the Mann-Whitney test, receiver operating characteristic (ROC) curve, and multiple linear regression.

The expression of c-Myc (3.53 ± 2.78 vs 0.93 ± 0.50), PVT1 (10.94 ± 8.49 vs 0.91 ± 0.48), CCAT2 (11.77 ± 10.00 vs 0.92 ± 0.95), and TCF7L2 (6.48 ± 4.30 vs 1.27 ± 0.96) was significantly higher in OSCC samples compared to OLP (P < 0.001). Conversely, miR-33 expression was significantly lower in OSCC samples (0.24 ± 0.25 vs 4.90 ± 3.90). There was a significant correlation between c-Myc, CCAT2, PVT1, and miR-33 expression and clinicopathological characteristics of OSCC specimens. In OSCC samples, c-Myc, PVT1, CCAT2, and TCF7L2 showed a significant positive correlation with each other, while miR-33 expression was negatively correlated with the overexpression of other genes. The area under the curve (AUC) for c-Myc, PVT-1, CCAT2, miR-33, and TCF7L2 were 0.917, 1.000, 0.979, 0.006, and 0.929, respectively.

Our findings suggest that c-Myc and LncRNAs (TCF7L2, PVT1, and CCAT2) are upregulated and miR-33 is downregulated in OSCC compared to OLP samples. These genes may serve as potential genetic biomarkers for diagnosis and prediction of clinicopathological features of OSCC.

Loganin (LG), a natural compound derived from Cornus officinalis Sieb. et Zucc., possesses diverse pharmacological properties, such as anti-inflammatory, anti-hypertrophic, and antioxidant effects. However, the role of LG in the pathogenesis of Heart Failure (HF) remains unclear. The current work aimed to explore the underlying mechanism of LG in pressure overload-induced HF, both in vivo and in vitro, using transverse aortic constriction (TAC) surgery or isoproterenol (ISO) administration. Following eight weeks of TAC surgery, histological assessments, including hematoxylin and eosin staining, wheat germ agglutinin staining, TUNEL assay, and Masson's trichrome staining, were conducted to evaluate the extent of cardiomyocyte remodeling. Additionally, RT-PCR and WB analyses were performed to detect the levels of various targets. Furthermore, H9C2 cardiomyocytes were treated with ISO to induce hypertrophy, and the effects of LG on cell viability, α-smooth muscle actin (α-SMA) expression, and molecular targets were investigated. Our findings revealed that LG treatment at 40 mg/kg/day significantly attenuated cardiac dysfunction, decreased left ventricular collagen deposition in both interstitial and perivascular spaces. Mechanistically, LG mitigated ISO-induced toxicity in H9C2 cardiomyocytes, decreasing cellular hypertrophy and α-SMA expression. Moreover, we observed a downregulation of Sirtuin 1 (Sirt1) at the molecular level, accompanied by reduced phosphorylation of Akt and transforming growth factor-β1 (TGF-β1). Notably, the administration of the Sirt1 inhibitor, EX527, effectively abolished the protective effects of LG. Therefore, the cardio-protective effects of LG were mediated through the activation of the Sirt1/Akt/TGF-β1 signaling pathway, leading to reduced fibrosis and improved cardiac function.

To explore the association of transforming growth factor β1 (TGF-β1) with left ventricular geometry (LVG) and left ventricular function (LVF) in cases having essential hypertension.

This retrospective study of 213 cases of essential hypertension, according to echocardiogram measurements, were split into normal geometry (NG), concentric remodeling (CR), eccentric hypertrophy (EH), and concentric hypertrophy (CH) groups. General clinical data of each patient was analyzed and office blood pressure measurements were performed. Detection of blood biochemistry and serum TGF-β1 content was conducted. The association of TGF-β1 with LVG and LVF parameters was assessed.

In contrast to the NG and CR groups, the TGF-β1 concentration was higher in the EH and CH groups, and it was most pronounced in the CH group. The TGF-β1 was positively linked to E/e' (r = 0.506, p < 0.001), whereas left ventricular global longitudinal strain (GLS) (r = -0.447, p < 0.001) was negatively correlated. Moreover, serum TGF-β1 levels were independently linked to EH and CH.

TGF-β1 was associated with abnormal LVG and LVF in cases of essential hypertension, indicating that it may induce LVG and LVF abnormalities.

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by vascular remodeling and involves Endothelial-to-Mesenchymal transition (EndMT) in pulmonary artery endothelial cells (PAECs). EndMT is a complex cell differentiation process, mainly showing the detachment of endothelial cell migration and reducing endothelial cell characteristics to varying degrees, acquiring mesenchymal cell characteristics. In addition, numerous studies have reported that eIF3a over expression plays an important role in the occurrence and development of fibrotic diseases, cancer, and degenerative lesions, however, the mechanisms of eIF3a affecting the dysfunction of pulmonary arterial endothelial cells remains largely unknown. Therefore, we aimed to demonstrate the underlying mechanisms of eIF3a-knockdown inhibiting EndMT by regulating TGFβ1/SMAD signal pathway in PAH.

In this study, we screened the potential target genes associated with idiopathic pulmonary arterial hypertension (IPAH) by WGCNA to provide a reference for the diagnosis and treatment of PAH. By constructing WGCNA, which indicated that the blue module (module-trait associations between modules and clinical feature information were calculated to selected the optimum module) is most closely associated with IPAH, we further screened out 10 up-regulated candidate biomarker genes. Male SD rats were randomly assigned to four groups: Control, Monocrotaline (MCT), AAV1-shRNA-NC group and AAV1-shRNA-eIF3a group. The eIF3a-knockdown rat model was constructed by adeno-associated virus type-1 (AAV1) infection, PAH was evaluated according to hemodynamic alteration, right heart hypertrophy and histopathological changes in the lung tissue. Hematoxylin eosin (H&E) staining was used to assess the morphological changes of pulmonary arteries in rats of each treatment group. Co-localization of eIF3a with alpha-small muscle action (α-SMA) and co-localization of eIF3a with endothelial marker (CD31) were detected by double-label immunofluorescence. Immunohistochemistry (IHC) and Western blot (WB) experiments were performed to assess the expression of eIF3a, EndMT and TGFβ1/SMAD signal related proteins. In vitro, primary rat pulmonary artery endothelial cells (PAECs) were transfected with si-eIF3a to investigate the effects of eIF3a-knockdown on hypoxia-induced EndMT in PAECs and further elucidate its underlying molecular mechanisms.

By WGCNA analysis, we screened the up-regulated hub genes of TMF1, GOLGB1, ARMC8, PRPF40 A, EIF3 A, ROCK2, EIF5B, CCP110, and KRR1 associated with PAH, and in order to verify the potential role of eIF3a in the development of pulmonary arterial hypertension, MCT-induced PAH rat model was constructed successfully. The expression of eIF3a was increased in MCT-treated lungs. Knockdown of eIF3a significantly inhibited the pulmonary arterial hypertension and vascular remodeling in MCT-induced PAH rat model, ameliorated MCT-induced increases of right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH) in rats. Double-labeled immunofluorescence showed eIF3a was mostly co-localized with CD31, this result indicated that the development of MCT-induced PAH was related to the regulation of PAECs function (most likely associated with the change of EndMT in endothelial cells). WB showed that the expressions of EndMT related proteins were significantly increased by regulating TGFβ1/SMAD signaling pathway in MCT-induced PAH rat lung tissues, however, knockdown of eIF3a markedly attenuated these changes. In addition, we observed the same results in rat PAECs with chronic hypoxia exposure. These results indicate that eIF3a-knockdown inhibited EndMT by regulating TGFβ1/SMAD signaling pathway in PAECs, thereby improving the development of MCT-induced PAH.

Knockdown of eIF3a inhibited EndMT in PAECs regulating TGFβ1/SMAD signaling pathway, significantly alleviated the changes of RVSP, RVH and vascular remodeling in MCT-induced PAH rats, eIF3a may be a promising and novel therapeutic target for the treatment of PAH.

In this work, 5-hydroxydopamine was employed as a crosslinking agent to bind chitosan and sulfonated polymers to fabricate thin gel layers (TGLs) featuring heparin-mimic structures. By controlling the distribution of exposed chemical moieties (phenolic hydroxyl, amino, and sulfonic groups), the growth of the endothelial cell (EC) and smooth muscle cell (SMC) on the TGLs surfaces could be modulated. Such modulation effectively maintained the quantity and proportion of the two cell types within a reasonable range, thereby offering a potential avenue for promoting re-endothelialization. The prepared TGLs showed improved hydrophilicity as well as hemocompatibility. For cytocompatibility test, TGLs led to a notable promotion of the growth of human umbilical vein endothelial cells (HUVECs) and exerted substantial inhibitory effects on the proliferation of human umbilical artery smooth muscle cells (HUASMCs). The ratio of HUVECs to HUASMCs rose from 0.184 to 1.97. The enhanced hemocompatibility was attributed to the incorporation of exposed functional groups. Regarding the highly selective effects, these were ascribed to the synergistic influence of high sulfonation degree and the presence of amino groups and phenolic hydroxyl groups. The current work illustrated a simple method for synthesizing a multifunctional biomimetic polymer material that offers the promise of broader biomedical research applications.

Adenomyosis is characterized by the invasion of endometrial glands and stroma into the myometrium. Its clinical manifestations often include dysmenorrhoea, excessive menstrual bleeding and infertility. Reduced pregnancy and live birth rates and an increased miscarriage rate are observed in women with adenomyosis. This review summarizes relevant advances and presents the underlying mechanisms of adenomyosis-associated infertility from an immunological perspective. Individuals with adenomyosis exhibit imbalances in immune cell subpopulations and the endocrine hormone-immunomodulatory axis. These immunological alterations may be key contributors to, or at least accomplices in, impaired endometrial receptivity. In addition, adenomyosis often occurs in association with endometriosis, uterine leiomyoma or endometrial polyps, which are pathogenetically relevant; their similarities and differences are discussed from an immunological perspective. The clinical diagnostic criteria of adenomyosis are not perfect, and the pathogenesis remains to be fully explored. Therefore screening for effective targets for early diagnosis and treatment at the cellular and molecular levels from the immunological point of view holds great potential, which will be of great importance in preventing this disease and improving women's reproductive health.

SSc is an autoimmune connective tissue disease involving multiple organs. The most common clinical symptom of SSc is progressive fibrosis of the skin, and the pathologically manifestations of skin were activation and proliferation of fibroblasts and continuous proliferation of extracellular matrix. TGF-β can promote the proliferation and activation of fibroblasts, causing excessive deposition of collagen and structural proteins. Therefore, exploring the specific mechanism of TGF-β-related pathway on fibrosis is of great significance for improving skin fibrosis in SSc.

Genes related to TGF-β pathway were screened through bioinformatics analysis, and SSc phenotypes were verified in vivo and in vitro. The relevant molecular mechanisms were preliminarily discussed in combination with transcriptome sequencing.

Human cysteine-rich secreted protein LCCL domain protein 2 (CRISPLD2) was found increased reactivity in TGF-β-induced fibroblasts, and the expression of ACTA2 (ɑ-SMA) decreased significantly in TGF-β-mediated fibroblasts with up-regulation of CRISPLD2.

CRISPLD2 was found to have increased reactivity in TGF-β-induced fibroblasts, and we further confirmed that CRISPLD2 can participate in TGF-β-induced fibroblast fibrosis from multiple perspectives and levels in negative feedback regulation, and investigated the mechanism of CRISPLD2 in fibrosis.

Hepatic fibrosis resulting from human mansonic schistosomiasis significantly impairs liver function and contributes substantially to morbidity associated with helminth infections. This pathological state develops following the deposition of helminth eggs within hepatic tissues, triggering a granulomatous inflammatory reaction. Schistosomiasis, a neglected tropical disease affecting approximately 240 million individuals globally, represents a major public health challenge. Although praziquantel (PZQ) is recommended by the World Health Organization (WHO) as the primary treatment for helminth infections, additional therapies are required to address the associated liver fibrosis. This study investigated the efficacy of tetramethylpyrazine (TMP), a natural compound known for its anti-inflammatory, antifibrotic, and hepatoprotective properties in various experimental models, in mitigating hepatic fibrosis induced by mansonic schistosomiasis. Our in vivo experiments demonstrated that TMP treatment significantly reduced hepatic granuloma size, as evidenced by histological analysis. Furthermore, our in vitro studies showed that TMP increased levels of the anti-inflammatory cytokine IL-10 while decreasing levels of the profibrotic cytokine IL-13 in a concentration-dependent manner. Immunofluorescence analysis also revealed that TMP effectively inhibited collagen deposition. Collectively, these findings suggest that TMP exhibits potential as an anti-inflammatory and antifibrotic agent for hepatic fibrosis resulting from Schistosoma mansoni infection.

Pulmonary fibrosis (PF) is a chronic pulmonary disease characterized by excessive extracellular matrix (ECM) deposition, with cigarette smoking being a major risk factor and no effective treatment at present. Transforming growth factor beta 1 (TGF-β1) plays a key role in PF and regulating oxidative stress. This study investigated the effects and mechanisms of Artemisia rupestris L. ethanol extract (ER) on cigarette smoke (CS)-induced PF. We used pull-down and LC-MS analyses to screen and identify compounds that bind to TGF-β1 in ER. We demonstrated that ER inhibits CS-induced PF, lung inflammation, and oxidative stress, thereby improving pulmonary structural injury. The ER inhibits fibroblast activation and fibroblast-to-myofibroblast transition (FMT), reducing collagen deposition for the treatment of PF. We identified the active ingredient in ER that binds to TGF-β1, namely, Luteolin 7-glucuronide (LG). LG inhibits the TGF-β1 signaling pathway through targeted binding to TGF-β1, downregulates the expression of downstream proteins (including collagen I, α-SMA, MMP-2, and MMP-9), and inhibits fibronectin expression. It also inhibits fibroblast activation and FMT, enhances E-cadherin expression to promote fibroblast adhesion, and suppresses collagen deposition, alleviating PF. Based on these findings, we propose that LG might be a promising therapeutic drug candidate for treating PF.

This study investigates differences in reproductive performance, testicular histology, and transcriptomic profiles between male Subei (SB; semi-wild) yaks and two domestic yaks, Gannan (GN) and Qinghai (QH). Key metrics including mating age, utilization time, breeding capacity, morphometric traits, and testicular indices were analyzed. SB yaks exhibited superior reproductive metrics, including earlier sexual maturity, prolonged utilization periods, and enhanced breeding capacity compared to GN and QH (P < 0.05). Morphologically, SB yaks demonstrated significantly greater body weight, and testicular dimensions. Compared with GN and QH yaks, the seminiferous tubules of SB yaks exhibited significantly larger spermatogenic cells and luminal cavities, along with a notably higher sperm density within the luminal cavity. Transcriptomic analysis identified 2,403 and 4,428 differentially expressed genes (DEGs) in GN vs. SB and QH vs. SB comparisons, respectively. Eight key genes (TPPP3, SMAD3, PAFAH1B3, BMP7, ARSA, CTNNB1, SMAD4, STAT3) and three pathways (Hippo, pluripotency regulation, TGF-β) were implicated in testicular development and spermatogenesis. These findings underscore the genetic and physiological advantages of SB yaks, offering insights for enhancing male yak reproductive performance.

Fibrosis is a partially manageable process that leads to scarring and tissue hardening by prompting myofibroblasts to deposit significant amounts of extracellular matrix (ECM) following injury. It results in detrimental consequences and pathological characteristics, which hinder the functioning of associated organs and increase mortality rates. Runt-related transcription factors (RUNX) are part of a highly conserved family of heterodimer transcription factors, comprising RUNX1, RUNX2, and RUNX3. They are involved in several biological processes and undergo various forms of post-translational modification. RUNX regulates multiple targets and pathways to impact fibrosis, indicating promise for clinical application. Therefore, its significance in the fibrosis process should not be disregarded. The review begins with an objective description of the structure, transcriptional mechanism, and biological function of RUNX1, RUNX2, and RUNX3. A subsequent analysis is made of their physiological relationship with heart, lung, kidney, and liver, followed by a focus on the signaling mechanism of RUNX in regulating fibrosis of these organs. Furthermore, potential agents or drugs targeting RUNX for treating organ fibrosis are summarized, along with an evaluation of the therapeutic prospects and potential value of RUNX in fibrosis. Further research into RUNX could contribute to the development of novel therapeutic approaches for fibrosis.

Renal fibrosis (RF), characterized by excessive deposition of extracellular matrix leading to tissue damage and scar formation, represents a refractory disease and a pivotal pathological basis for the progression to end-stage renal disease. The pathogenesis of RF is intricate, prominently implicating multiple key signaling pathways, including adenosine monophosphate-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR), phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), transforming growth factor-β1/small mother against decapentaplegic (TGF-β1/Smad), toll-like receptor 4/nuclear factor kappa B (TLR4/NF-κB), wingless integrated/β-catenin (Wnt/β-catenin), hypoxia-inducible factor-1α (HIF-1α), Hedgehog, and mitogen-activated protein kinase (MAPK). The current Western medical practices primarily rely on supportive and replacement therapies, which are often costly and suboptimal in efficacy. In contrast, traditional Chinese medicine (TCM), with its inherent advantages of multi-target, multi-pathway, and multi-effect modulation, emerges as a promising new strategy for RF treatment. However, a systematic, comprehensive, and detailed summary of these advancements remains absent. Therefore, this review consolidates the recent research progress on TCM modulation of RF-related signaling pathways, aiming to provide a theoretical foundation for further investigations into RF and the development of TCM interventions.

The spleen's complex structure and limited regenerative ability hinder its regrowth at the site of injure, affecting patient quality of life and risk severe complications. The spleen's stroma primarily consists of reticular and fibrillar collagen, supporting its microvascular network. Inspired by such biophysical environment, this work develops an inducible scaffold featuring an interpenetrating network structure of fibrous and reticular collagen, which is loaded with vascular endothelial cell membranes to facilitate in situ regeneration. The regenerated parenchyma includes red pulp, white pulp, and a vascular system. The scaffold effectively reduces oxidative stress at the injury site, recruits cells to degrade the scaffold, and promotes tissue integration, thereby accelerating spleen regeneration. Additionally, the regenerated tissue compensates for the spleen's functions, enhancing its ability to clear abnormal red blood cells and platelets. Proteomics and RNA sequencing analyses reveal that the scaffold induced the upregulation of key pathways, including the Wnt signalling pathway, Statin pathway, and amino acid metabolism pathway. This activation mobilizes splenic cells metabolism, enhances immune cell activity, and facilitates the remodeling of the extracellular matrix. Moreover, the incorporated cell membrane components promote splenic blood vessels regeneration by upregulating the neural crest cell differentiation pathway within the tissue.

Haizao Yuhu Decoction (HYD) is a traditional Chinese herbal formula known for regulating Qi and dispersing stasis.

This study investigates the effects of HYD on silica-induced lung injury and the underlying mechanisms.

The main constituents of HYD were identified using ultra-performance liquid chromatography Q-Exactive mass spectrometry (UPLC-QE-MS). Network pharmacology was employed to predict the targets and pathways through which HYD ameliorates silicosis, which were validated in a silica-induced lung injury mouse model and a TGF-β1-induced alveolar epithelial cell model. Pathological evaluation was conducted using hematoxylin-eosin (H&E) and Masson staining, while inflammatory cytokines and fibrosis were assessed via enzyme-linked immunosorbent assay (ELISA) and hydroxyproline quantification. Western blotting (WB) was performed to analyse protein expression levels of targeted markers. Proliferation and migration capabilities of MLE12 cells treated with HYD and its bioactive constituents (glycitein, diosmetin, and limonin) were assessed using cell counting kit-8 (CCK-8) and wound healing assays.

HYD significantly alleviated silica-induced lung injury, reducing inflammatory response and collagen deposition. A total of 176 constituents were identified in HYD, with 111 being pharmacologically active and linked to 1397 potential therapeutic targets, 107 associated with silicosis. Enrichment analyses highlighted the TGF-β1/Smad pathway and epithelial-mesenchymal transition (EMT) in HYD's anti-silicosis effects, which was validated by the restoration of TGF-β1, p-Smad2/Smad2, p-Smad3/Smad3, E-cadherin, and Vimentin following HYD treatment. Additionally, glycitein, diosmetin, and limonin inhibited the proliferation and migration of TGF-β1-induced MLE12 cells and suppressed the activation of TGF-β1/Smad pathway and EMT.

HYD effectively alleviates silica-induced lung injury by specifically inhibiting the TGF-β1/Smad pathway and EMT process.

The recent introduction of the term metabolic-dysfunction-associated steatotic liver disease (MASLD) has highlighted the critical role of metabolism in the disease's pathophysiology. This innovative nomenclature signifies a shift from the previous designation of non-alcoholic fatty liver disease (NAFLD), emphasizing the condition's progressive nature. Simultaneously, MASLD has become one of the most prevalent liver diseases worldwide, highlighting the urgent need for research to elucidate its etiology and develop effective treatment strategies. This review examines and delineates the revised definition of MASLD, exploring its epidemiology and the pathological changes occurring at various stages of the disease. Additionally, it identifies metabolically relevant targets within MASLD and provides a summary of the latest metabolically targeted drugs under development, including those in clinical and some preclinical stages. The review finishes with a look ahead to the future of targeted therapy for MASLD, with the goal of summarizing and providing fresh ideas and insights.

Heterotopic ossification (HO) is characterized by the abnormal growth of ectopic bone in non-skeletal soft tissues through a fibrotic pathway and is a frequent complication in a wide variety of musculoskeletal injuries. We have previously demonstrated that TGFβ levels are elevated in the soft tissues following extremity injuries. Since TGFβ mediates the initial inflammatory and wound-healing response in the traumatized muscle bed, we hypothesized that targeted inhibition of the TGFβ pathway may be able to abrogate the unbalanced fibrotic phenotype and bone-forming response observed in post-traumatic HO. Primary mesenchymal progenitor cells (MPCs) harvested from debrided traumatized human muscle tissue were used in this study. After treatment with TGFβ inhibitors (SB431542, Galunisertib/LY2157299, Halofuginone, and SIS3) cell proliferation/survival, fibrotic formation, osteogenic induction, gene expression, and phosphorylation of SMAD2/3 were assessed. In vivo studies were performed with a Sprague-Dawley rat blast model treated with the TGFβ inhibitors. The treatment effects on the rat tissues were investigated by radiographs, histology, and gene expression analyses. Primary MPCs treated with TGFβ had a significant increase in the number of fibrotic nodules compared to the control, while TGFβ inhibitors that directly block the TGFβ extracellular receptor had the greatest effect on reducing the number of fibrotic nodules and significantly reducing the expression of fibrotic genes. In vivo studies demonstrated a trend towards a lower extent of HO formation by radiographic analysis up to 4 months after injury when animals were treated with the TGFβ inhibitors SB431542, Halofuginone and SIS3. Altogether, our results suggest that targeted inhibition of the TGFβ pathway may be a useful therapeutic strategy for post-traumatic HO patients.

Hypertrophic scarring (HS) is a fibrotic skin disorder characterized by excessive deposition of extracellular matrix (ECM), leading to symptoms such as pain, itching, and skin contraction. HS can also result in restricted joint mobility and cosmetic deformities, imposing psychological and economic burdens on patients. Additionally, it increases wound care costs, and currently, no ideal treatment options exist. Therefore, HS is not only a clinical care issue but also a societal problem, with significant challenges related to its management and prevention. In this study, a custom-made cepharanthine ointment was applied to a rabbit ear scar model to investigate its effects on morphology, histology, and protein expression in HS. Additionally, the mechanism underlying the effect of cepharanthine on affected fibroblasts and the expression of ECM proteins was explored in vitro models of fibrosis. Animal experiments demonstrated that cepharanthine significantly reduced the tissue scar hypertrophy index and collagen content, improved the arrangement of fibroblasts, and inhibited ECM production. Cellular experiments indicated that cepharanthine effectively downregulated key proteins in the TGF-β/SMAD pathway, decreased ECM protein expression, and suppressed fibroblast proliferation and migration. Cepharanthine can prevent HS by reducing ECM deposition through the TGF-β/SMAD signalling pathway.

Mesenchymal stem cell (MSC) therapy represents a promising strategy for pulmonary fibrosis (PF) treatment, with hepatocyte growth factor (HGF) serving as a key mediator of MSC-mediated protection. However, the therapeutic efficacy of MSCs is limited by the complex PF microenvironment, and the mechanisms underlying this limitation remain unclear. This study investigates how the PF pathological microenvironment modulates the antifibrotic potential of placental mesenchymal stem cells of fetal origin (fPMSCs) through HGF regulation and elucidates the molecular mechanisms involved. Morphological analysis, flow cytometry, and multilineage differentiation assays were employed to characterize fPMSCs. Transforming growth factor-β1 (TGF-β1) was employed to simulate the PF microenvironment and activate fPMSCs in vitro. ELISA and Western blotting were used to analyze HGF expression, autophagy markers, and Smad signaling. Autophagosome formation was visualized via confocal microscopy and transmission electron microscopy. Co-immunoprecipitation (Co-IP) assays were performed to assess the interaction between p62 and HGF. The antifibrotic function of fPMSCs was further evaluated using a transwell co-culture system with MRC-5 fibroblasts in vitro and a bleomycin-induced PF mouse model in vivo. Phenotypic characterization confirmed that fPMSCs exhibited canonical MSC morphology, expressed CD73/CD90/CD105, lacked CD14/CD34/CD45/HLA-DR, and differentiated into adipogenic, osteogenic, and chondrogenic lineages. TGF-β1 treatment robustly downregulated the antifibrotic capacity, HGF protein expression, and paracrine secretion in fPMSCs. Recombinant HGF enhanced antifibrotic effects, while an HGF-neutralizing antibody abolished them. TGF-β1 induced autophagy in fPMSCs, promoting HGF degradation via p62 interaction and impairing antifibrotic function in vitro and in vivo. Mechanistically, Smad3 phosphorylation mediated the regulation of autophagy and HGF expression in TGF-β1-treated fPMSCs. Our findings demonstrate that TGF-β1 impairs the antifibrotic function of fPMSCs via autophagy-dependent HGF degradation and Smad3 signaling. Conversely, autophagy inhibition restores HGF levels and enhances fPMSCs' therapeutic efficacy in a preclinical PF model. Targeting autophagy inhibition emerges as a promising therapeutic strategy to counteract pulmonary fibrosis.