Fibroblast-like synoviocytes (FLS) display aggressive phenotypes contributing to synovitis and joint destruction in rheumatoid arthritis (RA). Disrupted mitochondrial homeostasis has been proposed to aggravate the RA pathogenesis, however, the underlying mechanism remains to be elucidated. This study aimed to elucidate the role of mitophagy receptor FUN14 domain-containing 1 (FUNDC1) on RA-FLS migration and invasion.

We analyzed the correlation of synovial FUNDC1 expression with joint destruction and disease activity in RA patients. Single cell sequencing data analysis combined with immunofluorescence indicated the specific expression and localization of FUNDC1 in synovial tissue and RA-FLS. The roles of FUNDC1 in the migration, invasion, and cytokine secretion of RA-FLS were examined by patient-derived primary culture as well as SCID mouse models. We investigated the effects and mechanism of FUNDC1 on mitophagy and mitochondrial quality control network in primary RA-FLS.

We found that the FUNDC1 was mainly expressed in FLS and exhibited a decreased level in RA synovium, which was correlated with severe joint destruction. Deficiency of FUNDC1 enhanced migration, invasion as well as secretion of matrix metalloproteinases in RA-FLS. On the contrary, overexpression of FUNDC1 in RA-FLS with low FUNDC1 inhibited the migration, invasion and secretion capacity of RA-FLS. Mechanistically, repressed FUNDC1 level in RA-FLS impaired mitophagy, imbalanced mitochondrial quality control, and increased mitochondrial reactive oxygen species (mtROS) production, leading to the overactivation of the MAPK pathway. Treatment with mtROS scavenger mtTEMPO can reverse this process and diminish the invasiveness of RA-FLS.

Deficiency of FUNDC1 dysregulates mitochondrial quality-control system and induces aggressive phenotype of RA-FLS, resulting in joint destruction during RA progression.

Reperfusion through thrombolytic therapy or primary percutaneous coronary intervention is commonly used to deal with acute myocardial infarction. However, the reperfusion procedure is accompanied by myocardial ischemia-reperfusion injury (MIRI). Currently, there is no therapeutics that can effectively deal with MIRI in clinical practice. Herein, the potential of ceria nanoparticles (CNPs) coated by different ligands in the treatment of rat MIRI is evaluated. The results demonstrate that CNPs can effectively modulate the oxidative stress in the heart tissue through the elimination of reactive oxygen species (ROS) and stimulation of endogenous antioxidant system. The inhibition of oxidative stress results in the reduction of p-Drp1 (Ser 616) which is critical in driving the fission and fragmentation of mitochondria. The improved mitochondrial dynamics saves the cardiomyocytes from apoptosis and reduces the acute injury of left ventricular wall during the MIRI. The ejection function of the left ventricle for both the short-term and long-term MIRI rats is well preserved. We therefore believe based on these results that the administration of CNPs is beneficial in the attenuation of MIRI during the acute stage. These findings provide useful information for the future fabrication of inorganic antioxidant nanomedicine for the treatment of MIRI.

Microvascular endothelial cells dysfunction can significantly worsen ischaemic stroke outcomes by disrupting tight junctions and increasing the acquisition of adhesion molecules, accelerating blood-brain barrier (BBB) disruption and pro-inflammatory response. The identification of drugs that improve endothelial cell function may be crucial for ischaemic stroke. It has been validated that empagliflozin (EMPA), a novel antidiabetic drug, protects endothelial cells regardless of the diabetic status of the patient. However, the impact of EMPA on stroke outcomes is unclear. We hypothesized that EMPA would exert a beneficial effect on ischaemic stroke outcome by protecting microvascular endothelial cells against tight junction disruption and the increase of adhesion molecules.

Young adult male mice were administered with EMPA or vehicle (dimethyl sulfoxide) daily for 7 days before being subjected to transient middle cerebral artery occlusion (tMCAO). Neurological deficits were evaluated for up to 28 days post-tMCAO. Infarct volume, BBB disruption, and inflammatory status were assessed 1 day after tMCAO.bEnd.3 cells and primary brain microvascular endothelial cells were treated with EMPA or vehicle under oxygen and glucose deprivation/reperfusion (OGD/R), and the lactate dehydrogenase release, transendothelial electrical resistance, leakage of fluorescein isothiocyanate-dextran, and tight junction and adhesion molecules proteins were examined. Mechanistic studies probing the effect of EMPA on endothelial cells were conducted by RNA-seq. EMPA treatment before ischaemia markedly improved infarct volume, BBB disruption, and inflammation 1-day post-tMCAO, and further enhanced neurobehavioral function up to 28 days. Pre-treatment of EMPA attenuated endothelial cell dysfunction under OGD/R conditions. In mechanistic terms, RNA-seq data from isolated cerebral microvessels revealed that the Wnt/β-catenin signalling pathway was preserved in the EMPA group, in contrast to the vehicle group. Pre-treatment with EMPA inhibited β-catenin ubiquitination and promoted β-catenin translocation from the cytoplasm to the nucleus to improve endothelial cell function. Importantly, the β-catenin inhibitor XAV-939 eliminated this protective function of EMPA.

EMPA administration before tMCAO attenuated ischaemia/reperfusion-induced BBB disruption and inflammation via β-catenin-mediated protection of cerebral microvascular endothelial cells. Therefore, EMPA shows potential for improving stroke outcomes as an adjunctive preventive strategy.

Cellular senescence is the permanent cessation of cell proliferation and growth. Senescent cells accumulating in tissues and organs with aging contribute to many chronic diseases, mainly through the secretion of a pro-inflammatory senescence-associated secretory phenotype (SASP). Senotherapeutic (senolytic or senomorphic) strategies targeting senescent cells or/and their SASP are being developed to prolong healthy lifespan and treat age-related pathologies. Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a new class of anti-diabetic drugs that promote the renal excretion of glucose, resulting in lower blood glucose levels. Beyond their glucose-lowering effects, SGLT2 inhibitors have demonstrated protective effects against cardiovascular and renal events. Moreover, SGLT2 inhibitors have recently been associated with the inhibition of cell senescence, making them a promising therapeutic approach for targeting senescence and aging. This review examines the latest research on the senotherapeutic potential of SGLT2 inhibitors.

Cardiovascular disease remains the leading cause of death globally, and drugs for new targets are urgently needed. Mitochondria are the primary sources of cellular energy, play crucial roles in regulating cellular homeostasis, and are tightly associated with pathological processes in cardiovascular disease. In response to physiological signals and external stimuli in cardiovascular disease, mitochondrial quality control, which mainly includes mitophagy, mitochondrial dynamics, and mitochondrial biogenesis, is initiated to meet cellular requirements and maintain cellular homeostasis. Traditional Chinese Medicine (TCM) has been shown to have pharmacological effects on alleviating cardiac injury in various cardiovascular diseases, including myocardial ischemia/reperfusion, myocardial infarction, and heart failure, by regulating mitochondrial quality control. Recently, several molecular mechanisms of TCM in the treatment of cardiovascular disease have been elucidated. However, mitochondrial quality control by TCM for treating cardiovascular disease has not been investigated. In this review, we aim to decipher the pharmacological effects and molecular mechanisms of TCM in regulating mitochondrial quality in various cardiovascular diseases. We also present our perspectives regarding future research in this field.

Empagliflozin is an effective treatment for heart failure with preserved ejection fraction (HFpEF), but its definite mechanism of action is unclear. Systemic microvascular dysfunction strongly relates to HFpEF aetiology, and we hypothesised that empagliflozin improves microvascular function in HFpEF.

To investigate the effect of the sodium-glucose cotransporter-2 inhibitor empagliflozin on peripheral microvascular function in HFpEF.

This is a pre-post intervention study in patients diagnosed with HFpEF who are eligible for treatment with empagliflozin. Microvascular function assessment using laser speckle contrast analysis of the dorsal forearm during iontophoresis of vasoactive stimuli (acetylcholine, insulin sodium nitroprusside) was performed at baseline and after 3 months of empagliflozin treatment (10 mg daily). The primary outcome was the difference in blood flow measured in the forearm microvasculature between baseline and at follow-up (cutaneous vascular conductance, CVC). Secondarily we investigated quality-of-life based on the EQ-5D-5 L questionnaire at baseline and follow-up.

Twenty six patients finished the study according to protocol (mean age of 74 ± 7 years, 62% female). We observed a decreased blood flow response to acetylcholine after 3 months of empagliflozin (CVC: 0.77 ± 0.24 vs. 0.64 ± 0.20, p < 0.001). In contrast, the response to insulin improved (CVC: 0.61 ± 0.43 vs. 0.81 ± 0.32, p = 0.03), and the response to sodium nitroprusside remained stable after 3 months. No significant correlations were found between the changes in blood flow and quality of life.

This study shows that three months treatment with empagliflozin changed peripheral microvascular function in patients with HFpEF. Empagliflozin may enhance microvascular blood flow specifically via vascular actions of insulin, rather than a general effect on endothelial vasoregulation or smooth muscle cell function. As such, systemic microvascular dysfunction can be a modifiable factor in patients with HFpEF, while the clinical implications thereof warrant further investigations.

The trial was preregistered at clinicaltrials.gov (NCT06046612).

Ischemia-reperfusion (I/R) injury describes the pathological process wherein tissue damage, initially caused by insufficient blood supply (ischemia), is exacerbated upon the restoration of blood flow (reperfusion). This phenomenon can lead to irreversible tissue damage and is commonly observed in contexts such as cardiac surgery and stroke, where blood supply is temporarily obstructed. During ischemic conditions, the anaerobic metabolism of tissues and organs results in compromised enzyme activity. Subsequent reperfusion exacerbates mitochondrial dysfunction, leading to increased oxidative stress and the accumulation of reactive oxygen species (ROS). This cascade ultimately triggers cell death through mechanisms such as autophagy and mitophagy. Autophagy constitutes a crucial catabolic mechanism within eukaryotic cells, facilitating the degradation and recycling of damaged, aged, or superfluous organelles and proteins via the lysosomal pathway. This process is essential for maintaining cellular homeostasis and adapting to diverse stress conditions. As a cellular self-degradation and clearance mechanism, autophagy exhibits a dualistic function: it can confer protection during the initial phases of cellular injury, yet potentially exacerbate damage in the later stages. This paper aims to elucidate the fundamental mechanisms of autophagy in I/R injury, highlighting its dual role in regulation and its effects on both organ-specific and systemic responses. By comprehending the dual mechanisms of autophagy and their implications for organ function, this study seeks to explore the potential for therapeutic interventions through the modulation of autophagy within clinical settings.

MARCH5 is a key regulatory factor in mitochondria. However, the expression and function of MARCH5 in thyroid cancer (TC) are not yet clear. The research explores the role and the potential mechanism of MARCH5 in the tumorigenesis of TC. MARCH5 expression were measured by qRT-PCR and Western blot. CCK-8 kits were used to measure the cell viability. Cell scratch assay and Tanswell assay were used to measure cell migration and invasion, respectively. The pyroptosis related proteins (NLRP3, caspase-1, GSDMD) and mitochondrial autophagy related proteins (LC3-II, p62, parkin, pink1) were detected. The mitochondrial ROS GSH, MDA, and SOD were detected using commercial kits. Finally, a TC mouse model was constructed to detect the role of MARCH5 in tumor growth in vivo. The results displayed that the expression of MARCH5 was increased in TC patients and cells, and was significantly correlated with prognosis. Functional studies have found that MARCH5 inhibits oxidative stress levels and mitochondrial autophagy in TPC-1 cells. Further research has found that MARCH5 promotes the progression of thyroid cancer by degrading FUNDC1 and inhibiting the mitochondrial autophagy mediated pyroptosis pathway, regulating cell proliferation, migration, and invasion in TPC-1 cells. More importantly, interference with MARCH5 inhibits tumor growth and further development of TC in vivo. In conclusion, MARCH5 promotes the progression of thyroid cancer by degrading FUNDC1 and inhibiting the mitochondrial autophagy mediated pyroptosis, regulating cell proliferation, migration, and invasion. This study provides new theoretical basis for the treatment and prevention of TC in clinical practice.

Cardiovascular diseases (CVDs) are the leading cause of rising morbidity and mortality among humans worldwide; however, our approach to the pathogenesis, exploration, and management of CVDs still remains limited. As the heart consists of cardiomyocytes, cardiac fibroblasts, endothelial cells, smooth muscle cells, and several types of cells, different types of dysfunction in the interplay between organelles play an important damaging role, resulting in cardiac pathologies. The interplay between cellular organelles is intricate and vital for maintaining cellular homeostasis, as highlighted by multiple diseases linked to the dysfunction of both organelles. Many studies have revealed the potential mechanisms by which organelles communicate with each other and regulate the pathological processes of CVDs together. However, gaps remain in fully understanding the complexity of these interactions and translating these insights into therapeutic approaches. In this review, we summarized how the interplay between cellular organelles in the cardiomyocytes alters in various heart diseases. We find underexplored areas, such as the crucial signaling pathways governing organelle communication, and discuss their implications for disease future progression. Furthermore, we evaluate emerging potential medicines aimed at restoring organelle interactions. Finally, we propose future directions for researching to advance the development of novel medicines and therapies, addressing current gaps and providing a theoretical basis for improved clinical outcomes in CVDs.

Heart failure (HF) treatment remains one of the major challenges in cardiovascular disease management, and its pathogenesis requires further exploration. Cardiac metabolic remodeling is of great significance as a key pathological process in the progression of HF. The complex alterations of metabolic substrates and associated enzymes in mitochondria create a vicious cycle in HF. These changes lead to increased reactive oxygen species, altered mitochondrial Ca2+ handling, and the accumulation of fatty acids, contributing to impaired mitochondrial function. In this context, mitophagy plays a significant role in clearing damaged mitochondria, thereby maintaining mitochondrial function and preserving cardiac function by modulating metabolic remodeling in HF. This article aims to explore the role of mitophagy in cardiac metabolic remodeling in HF, especially in obesity cardiomyopathy, diabetic cardiomyopathy, and excessive afterload-induced heart failure, thoroughly analyze its molecular mechanisms, and review the therapeutic strategies and prospects based on the regulation of mitophagy.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors have demonstrated potential neuroprotective and cardioprotective effects in preliminary studies. This study evaluates the efficacy of empagliflozin (EMPA) in reducing ischemia/reperfusion damage in both the brain and heart using rat models. Ischemic stroke and myocardial infarction (MI) were induced in male Sprague-Dawley rats, which were randomized into three groups: (1) Control (no EMPA), (2) Acute treatment (EMPA, 10 mg/kg IV, administered 10 min before ischemia and 1 min before reperfusion), and (3) Chronic treatment (EMPA, 20 mg/kg in food for 7 days before ischemia). Stroke was induced by middle cerebral artery occlusion (MCAO) for one hour, followed by 3 h of reperfusion, and MI was induced by left coronary artery occlusion for 30 min, followed by 3 h of reperfusion. Brain and heart tissues were analyzed for anatomic size of myocardial infarction and stroke. In the brain, cerebral infarction was significantly smaller in both EMPA treatment groups compared to controls (acute: 3.7 ± 1.2%, chronic: 6.9 ± 2.1% vs. control: 14.5 ± 2.5%, p < 0.05). Edema was also reduced in the EMPA groups (acute: 5.5 ± 0.9%, chronic: 5.9 ± 0.8% vs. control: 9.6 ± 1.2%, p < 0.05). In the heart, MI size was significantly reduced in both EMPA groups (acute: 46.9 ± 2.0%, chronic: 48.8 ± 5.8% vs. control: 70.0 ± 2.6%, p < 0.05), and no-reflow size was smaller in the EMPA groups (acute: 36.3 ± 3.3%, chronic: 33.9 ± 4.3% vs. control: 53.4 ± 3.3%, p < 0.05). EMPA treatment, both acute and chronic, significantly reduces cerebral infarct volume and edema, as well as myocardial infarct size and no-reflow in rat models of ischemic stroke and myocardial ischemia/reperfusion, indicating substantial neuroprotective and cardioprotective effects.

Endothelial dysfunction-induced microcirculation impairment and the no-reflow phenomenon are the leading causes of cardiac ischemia/reperfusion (I/R) injury. There is an urgent need to elucidate the underlying mechanism of I/R-mediated endothelial dysfunction and to identify effective drugs for treatment. Scutellarin (SCU), a flavonoid compound, has been extensively studied because of its various pharmacological properties, including its potent protective effects on the cardiovascular system. However, the anti-endothelial dysfunction efficacy and mechanisms of action of SCU have not been investigated.

An in vivo I/R injury model was established using coronary artery ligation and release. An oxygen-glucose deprivation/oxygen-glucose resupply (OGD/OGR) approach was used to establish an in vitro I/R injury model. We evaluated the effects of SCU on endothelial dysfunction under I/R conditions, both in vivo and in vitro. SCU pretreatment promoted vasodilation and reperfusion of blood flow, inhibited myocardial injury and infarction, and improved cardiac function in I/R rats. Additionally, SCU inhibited cell membrane damage, reactive oxygen species (ROS) accumulation, inflammation, nitric oxide (NO) reduction, endothelin 1 (ET-1) elevation and increase in the expression levels of vascular endothelial growth factor (VEGF) and von willebrand factor (vWF) in endothelial cells. Mechanistically, SCU rescued the lysosomal flow and autophagic flux disrupted by I/R through upregulating cathepsin D (CTSD) levels. Knockdown of CTSD or treatment with the CTSD inhibitor pepstatin A (P.A) abrogated the protective effects of SCU on endothelial cells under I/R conditions.

We demonstrated that SCU, via upregulation of CTSD levels in endothelial cells, rescued autophagy-lysosomal function and alleviated I/R-mediated endothelial dysfunction. Thus, SCU is a potential therapeutic drug for the prevention and treatment of cardiac I/R injury.

Zishen Huoxue decoction (ZSHX) enhances cardiomyocyte viability following hypoxic stress; however, its upstream therapeutic targets remain unclear. Network pharmacology and RNA sequencing analyses revealed that ZSHX target genes were closely associated with mitophagy and apoptosis in the mitochondrial pathway. In vitro, ZSHX inhibited pathological mitochondrial fission following hypoxic stress, regulated FUN14 domain-containing protein 1 (FUNDC1)-related mitophagy, and increased the levels of mitophagy lysosomes and microtubule-associated protein 1 light chain 3 beta II (LC3II)/translocase of outer mitochondrial membrane 20 (TOM20) expression while inhibiting the over-activated mitochondrial unfolded protein response. Additionally, ZSHX regulated the stability of beta-tubulin through Sirtuin 5 (SIRT5) and could modulate FUNDC1-related synergistic mechanisms of mitophagy and unfolded protein response in the mitochondria (UPRmt) via the SIRT5 and -β-tubulin axis. This targeting pathway may be crucial for cardiomyocytes to resist hypoxia. Collectively, these findings suggest that ZSHX can protect against cardiomyocyte injury via the SIRT5-β-tubulin axis, which may be associated with the synergistic protective mechanism of SIRT5-β-tubulin axis-related mitophagy and UPRmt on cardiomyocytes.

Significant advancements in therapeutic approaches are imperative to address the prevalent impact of myocardial infarction (MI) on morbidity and mortality rates worldwide. This study explores the therapeutic potential of GATM/Gel hydrogel, focusing on its ability to enhance cardiac repair and functionality after MI through modulation of inflammatory and repair pathways.

The effects of GATM/Gel hydrogel on cardiac recovery were studied in a murine MI model. HA-CHO and gelatin solutions were mixed in situ using a dual syringe with a static mixing needle, and the resulting hydrogel was applied directly to the epicardium during MI modeling, followed by repositioning of the heart and closure of the thorax. Comprehensive in vivo assessments-including echocardiography, electrocardiography, and histopathological analysis-were combined with molecular techniques such as RT-qPCR, Western blotting, and immunofluorescence to elucidate the underlying mechanisms. Key cellular and molecular changes were tracked, focusing on macrophage polarization, angiogenesis, and modulation of the TNF/TNFR2 signaling pathway.

Employing the GATM/Gel hydrogel led to a substantial improvement in heart function, shown through enhanced ejection fraction and fractional shortening, and reduced infarction size compared to control groups. Mechanistically, the hydrogel promoted the polarization of anti-inflammatory M2 macrophages and stimulated angiogenesis. Moreover, treatment with GATM/Gel hydrogel altered the TNF/TNFR2 pathway, pivotal in mediating inflammatory responses and facilitating myocardial repair. The discoveries highlight the possibility of GATM/Gel hydrogels as an innovative remedy for MI, providing a twofold role in regulating inflammation and fostering recovery.

Skeletal muscle atrophy is a complication of obesity, partially induced by impaired mitophagy. This study investigates whether Berberine(BBR) protects mice from obese skeletal muscle atrophy and the underlying molecular mechanism. Twenty C57BL/6 mice were fed a high-fat diet until they weighed more than 20% of the average body weight of the control group. The mice were then divided into two groups and gavaged with BBR or vehicle for 8 weeks. 10 mice were used as controls. Fasting blood glucose was measured, an oral glucose tolerance test was performed, and the mice were measured for grip strength and exercise capacity. H&E and Oil Red O staining were used to observe the pathological changes of skeletal muscle. MURF1, FBXO32, BAX, BCL2, P62, LC3 and mitophagy receptor FUNDC1 were observed in mice. BBR was intervened in C2C12 myotubes. The role of FUNDC1 was verified by RNA interference. We found that BBR treatment increased grip strength and improved muscle function. BBR not only reduced weight gain, excessive lipid accumulation and hyperlipidemia, but also ameliorated obesity-induced skeletal muscle atrophy and apoptosis. BBR promoted autophagy and increased FUNDC1 protein expression. The same positive effects were observed after BBR intervening on C2C12 myotubes, whereas FUNDC1 RNA interference attenuated the anti-skeletal muscle atrophy effect of BBR. These results suggest that BBR ameliorated obesity-induced skeletal muscle atrophy in mice by modulating the skeletal muscle mitophagy receptor FUNDC1, which may be a potential therapeutic target for obesity-induced skeletal muscle atrophy.

Cancer cells utilize larger amounts of glucose than their normal counterparts, and the expression of GLUT transporters is a known diagnostic target and a prognostic factor for many cancers. Recent evidence has shown that sodium-glucose transporters are also expressed in different types of cancer, and SGLT2 has raised particular interest because of the current availability of anti-diabetic drugs that block SGLT2 in the kidney, which could be readily re-purposed for the treatment of cancer. The aim of this article is to perform a narrative review of the existing literature and a critical appraisal of the evidence for a role of SGLT2 inhibitors for the treatment and prevention of cancer. SGLT2 inhibitors block Na-dependent glucose uptake in the proximal kidney tubules, leading to glycosuria and the improvement of blood glucose levels and insulin sensitivity in diabetic patients. They also have a series of systemic effects, including reduced blood pressure, weight loss, and reduced inflammation, which also make them effective for heart failure and kidney disease. Epidemiological evidence in diabetic patients suggests that individuals treated with SGLT2 inhibitors may have a lower incidence and better outcomes of cancer. These studies are confirmed by pre-clinical evidence of an effect of SGLT2 inhibitors against cancer in xenograft and genetically engineered models, as well as by in vitro mechanistic studies. The action of SGLT2 inhibitors in cancer can be mediated by the direct inhibition of glucose uptake in cancer cells, as well as by systemic effects. In conclusion, there is evidence suggesting a potential role of SGLT2 inhibitors against different types of cancer. The most convincing evidence exists for lung and breast adenocarcinomas, hepatocellular carcinoma, and pancreatic cancer. Several ongoing clinical trials will provide more information on the efficacy of SGLT2 inhibitors against cancer.

In patients with acute myocardial infarction (AMI), thrombolytic therapy and revascularization strategies allow complete recanalization of occluded epicardial coronary arteries. However, approximately 35% of patients still experience myocardial ischemia/reperfusion (I/R) injury, which contributing to increased AMI mortality. Therefore, an accurate understanding of myocardial I/R injury is important for preventing and treating AMI. The death of each cell (cardiomyocytes, endothelial cells, vascular smooth muscle cells, cardiac fibroblasts, and mesenchymal stem cells) after myocardial ischemia/reperfusion is associated with apoptosis due to mitochondrial dysfunction. Abnormal opening of the mitochondrial permeability transition pore, aberrant mitochondrial membrane potential, Ca2+ overload, mitochondrial fission, and mitophagy can lead to mitochondrial dysfunction, thereby inducing mitochondrial apoptosis. The manifestation of mitochondrial apoptosis varies according to cell type. Here, we reviewed the characteristics of mitochondrial apoptosis in cardiomyocytes, endothelial cells, vascular smooth muscle cells, cardiac fibroblasts, and mesenchymal stem cells following myocardial ischemia/reperfusion.

Flaps are widely used in surgical wound repair, yet distal necrosis poses a significant postoperative challenge, stemming from potential factors such as inadequate blood perfusion, inflammation, ischemia/reperfusion (I/R) injury, mitochondrial impairment, and subsequent ferroptosis. Empagliflozin (EMPA), a sodium-glucose cotransporter 2 inhibitor, has pharmacological activities that promote angiogenesis, mitophagy, and inhibit inflammation, I/R injury, and ferroptosis. However, it is unclear whether EMPA can enhance flap survival. Here, we established a modified McFarlane flap model and applied EMPA to demonstrate its mechanism of action. 24 rats were evenly divided into four groups: the control, low-dose EMPA (10 mg/kg), high-dose EMPA (30 mg/kg), and inhibitor groups. Molecular biology experiments demonstrated that EMPA promoted the expression of angiogenesis-related factors vascular endothelial growth factor (VEGF) and CD34. Additionally, it also increased superoxide dismutase (SOD) activity and reduced malondialdehyde (MDA) levels, thus suppressing oxidative stress. EMPA further alleviated inflammation by downregulating the expression of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). In vitro experiments showed that EMPA promoted the proliferation of human umbilical vein endothelial cells (HUVECs) and reduce their reactive oxygen species (ROS) production. Further investigation demonstrated that EMPA improves flap prognosis by inducing the expression of the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway, further promoting mitophagy and inhibiting ferroptosis. These effects collectively contributed to the survival of the skin flap. Overall, our research elucidates the protective effects of EMPA on flap survival and its specific mechanisms, offering new insights into solving post-transplant flap necrosis.

Sodium/glucose co-transporter 2 (SGLT2) inhibitors have transformed heart failure (HF) treatment, offering sympatholytic effects whose mechanisms are not fully understood. Our previous studies identified Cyclic GMP-AMP synthase (cGAS)-derived neuroinflammation in the Subfornical organ (SFO) as a promoter of sympathoexcitation, worsening myocardial remodeling in HF. This research explored the role of central SGLT2 in inducing endothelial cGAS-driven neuroinflammation in the SFO during HF and assessed the impact of SGLT2 inhibitors on this process.

Hypertensive HF was induced in mice via Angiotensin II infusion for four weeks. SGLT2 expression and localization in the SFO were determined through immunoblotting and double-immunofluorescence staining. AAV9-TIE-shRNA (SGLT2) facilitated targeted SGLT2 knockdown in SFO endothelial cells (ECs), with subsequent analyses via immunoblotting, staining, and co-immunoprecipitation to investigate interactions with cGAS, mitochondrial alterations, and pro-inflammatory pathway activation. Renal sympathetic nerve activity and heart rate variability were measured to assess sympathetic output, alongside evaluations of cardiac function in HF mice.

In HF model mice, SGLT2 levels are markedly raised in SFO ECs, disrupting mitochondrial function and elevating oxidative stress. SGLT2 knockdown preserved mitochondrial integrity and function, reduced inflammation, and highlighted the influence of SGLT2 on mitochondrial health. SGLT2's interaction with cGAS prevented its ubiquitination and degradation, amplifying neuroinflammation and HF progression. Conversely, Empagliflozin counteracted these effects, suggesting that targeting the SGLT2-cGAS interaction as a novel HF treatment avenue.

This study revealed that SGLT2 directly reduced cGAS degradation in brain ECs, enhancing neuroinflammation in the SFO, and promoting sympathoexcitation and myocardial remodeling. The significance of the central SGLT2-cGAS interaction in cardiovascular disease mechanisms is emphasized.

Myocardial ischemia-reperfusion (MI/R) injury tends to affect cardiac function and leads to poor patient prognosis, and there is still no effectively targeted drug to develop anti-von Willebrand factor (VWF) aptamer in acute coronary heart disease. However, the newly anti-VWF aptamer BT200 is applied not only for stroke and hemophilia but also for antithrombolism function in clinical development. The role of BT200 in acute myocardial injury during MI/R is still unknown.

To investigate the cardioprotective effect of aptamer BT200 in a mouse model of MI/R.

C57BL/6 mice were subjected to 30-minute ischemia and 24-hour reperfusion to establish MI/R model. Mice were treated with intravenous injection of cy3-labeled BT200 and were observed by an in vivo imaging system at different time points. Then, mice were sampled and evaluated by echocardiography, Evans triphenyltetrazolium chloride staining, histopathologic, western blotting, and real-time quantitative polymerase chain reaction assays to detect cardiac injury and inflammation response after 24-hour reperfusion.

BT200 aptamer can enter and infiltrate into the ischemic myocardium after 24-hour reperfusion. BT200 was shown to inhibit VWF A1 activity and prolong bleeding time in MI/R mice. Moreover, BT200-treated mice had a significant reduction in infarct size and an improvement in cardiac function post-MI/R. BT200 treatment can also alleviate MI/R-induced microvascular obstruction, inflammation response, and cardiomyocyte apoptosis.

Pharmacologic targeting of VWF with BT200 alleviates acute MI/R injury in a murine model and may be a novel therapy strategy for acute myocardial infarction.

The in-hospital mortality rate in acute myocardial infarction (AMI) remains high despite the undoubted achievements in treatment of this disease achieved in the last 40 years. The dangerous complications of AMI remain cardiac microvascular injury (CMI) and intramyocardial hemorrhage (IMH). IMH is a widespread pathology that occurs in 42 - 57% of patients with ST-segment elevation myocardial infarction and percutaneous coronary intervention. IMH is associated with larger infarct size and contractile dysfunction. IMH is accompanied by inflammation. The appearance of IMH is depending on the duration of ischemia and requires reperfusion of the heart. IMH is accompanied by contractile dysfunction and adverse remodeling of the heart. The most likely cause of IMH is CMI. Pretreatment with ATL-146e, melatonin, tanshinone IIA, relaxin, empagliflozin, dapagliflozin, and astragaloside IV can mitigate I/R-induced CMI. CMI is accompanied by an increase in the myocardial and plasma proinflammatory cytokine levels and also the downregulation of tight junction proteins in cardiac vascular endothelial cells. However, there is no convincing evidence that proinflammatory cytokines trigger CMI. An increase in the proinflammatory cytokine levels and CMI could be two independent processes.

Mitochondrial dysfunction is linked to myocardial ischemia-reperfusion (I/R) injury. Checkpoint kinase 1 (CHK1) could facilitate cardiomyocyte proliferation, however, its role on mitochondrial function in I/R injury remains unknown.

To investigate the role of CHK1 on mitochondrial function following I/R injury, cardiomyocyte-specific knockout/overexpression mouse models were generated. Adult mouse cardiomyocytes (AMCMs) were isolated for in vitro study. Mass spectrometry-proteomics analysis and protein co-immunoprecipitation assays were conducted to dissect the molecular mechanism.

CHK1 was downregulated in myocardium post I/R and AMCMs post oxygen-glucose deprivation/re‑oxygenation (OGD/R). In vivo, CHK1 overexpression protected against I/R induced cardiac dysfunction, while heterogenous CHK1 knockout exacerbated cardiomyopathy. In vitro, CHK1 inhibited OGD/R-induced cardiomyocyte apoptosis and bolstered cardiomyocyte survival. Mechanistically, CHK1 attenuated oxidative stress and preserved mitochondrial metabolism in cardiomyocytes under I/R. Moreover, disrupted mitochondrial homeostasis in I/R myocardium was restored by CHK1 through the promotion of mitochondrial biogenesis and mitophagy. Through mass spectrometry analysis following co-immunoprecipitation, SIRT1 was identified as a direct target of CHK1. The 266-390 domain of CHK1 interacted with the 160-583 domain of SIRT1. Importantly, CHK1 phosphorylated SIRT1 at Thr530 residue, thereby inhibiting SMURF2-mediated degradation of SIRT1. The role of CHK1 in maintaining mitochondrial dynamics control and myocardial protection is abolished by SIRT1 inhibition, while inactivated mutation of SIRT1 Thr530 fails to reverse the impaired mitochondrial dynamics following CHK1 knockdown. CHK1 Δ390 amino acids (aa) mutant functioned similarly to full-length CHK1 in scavenging ROS and maintaining mitochondrial dynamics. Consistently, cardiac-specific SIRT1 knockdown attenuated the protective role of CHK1 in I/R injury.

Our findings revealed that CHK1 mitigates I/R injury and restores mitochondrial dynamics in cardiomyocytes through a SIRT1-dependent mechanism.

Considering that cardiac microvascular injury may play a more critical role than cardiomyocyte injury in the pathology of early ischaemia/reperfusion (I/R) injury, therapeutic strategies targeting the microvasculature are highly desirable. Palmitic acid-9-hydroxystearic acid (9-PAHSA) is a new class of bioactive anti-inflammatory lipids widely distributed in vegetables, fruits and medicinal plants, especially broccoli and apple. However, the pharmacological effects and underlying mechanisms of 9-PAHSA in protecting- against cardiac microvascular I/R injury have rarely been studied.

This study aimed to explore the potential effects and molecular mechanisms of 9-PAHSA on the coronary microvasculature after cardiac I/R injury.

Immunofluorescence staining, western blotting, and other experimental methods were used to evaluate the role and mechanism of 9-PAHSA in cardiac microvascular I/R injury in vivo and in vitro.

9-PAHSA administration significantly attenuated myocardial I/R-induced microvascular damage, as indicated by an impaired microvascular structure, reduced regional blood perfusion and decreased endothelial barrier function. In addition, 9-PAHSA administration protected the structure and function of coronary artery endothelial cells (CMECs) to resist I/R damage, an effect that was at least partially mediated by increased autophagy. Mechanistically, 9-PAHSA activated autophagy through the LKB1/AMPK/ULK1 pathway and promoted STING degradation via the autophagic‒lysosomal pathway.

To our best knowledge, this study is the first to report that 9-PAHSA attenuates cardiac microvascular I/R injury, potentially by activating LKB1/AMPK/ULK1-mediated autophagy-dependent STING degradation to suppress apoptosis. Thus, 9-PAHSA may be a promising therapeutic option for alleviating cardiac microvascular I/R injury.

We aimed to investigate the role of Rnf40 in hypertension-induced cerebrovascular endothelial barrier dysfunction and cognitive impairment.

We employed microarray data analysis and integrated bioinformatics databases to identify a novel E3 ligase, Rnf40, that targets Parkin. To understand the role of RNF40 in hypertension-induced cerebrovascular endothelial cell damage, we used pAAV-hFLT1-MCS-EGFP-3×Flag-mir30shRnf40 to establish an Rnf40-deficient model in spontaneously hypertensive rats (SHRs). We also evaluated the cerebrovascular endothelial barrier function, cerebral blood flow, and cognitive performance.

We observed reduced mitophagy in cerebrovascular endothelial cells of SHRs compared with that in Wistar-Kyoto rats. Rnf40 facilitated K48-linked polyubiquitination and degradation of Parkin, thereby inhibiting mitophagy. In the Rnf40-deficient SHR model, knocking down Rnf40 restored mitophagy in cerebrovascular endothelial cells. Additionally, levels of tight junction proteins and cerebrovascular endothelial barrier function improved following Rnf40 downregulation. Rnf40 depletion also improved global cognitive performance and restored cerebral blood flow in SHRs.

Our findings suggest that increased Rnf40 levels exacerbate hypertension-induced cerebrovascular endothelial barrier dysfunction by ubiquitinating Parkin.

Empagliflozin treatment before acute myocardial infarction mainly targets the endothelial cell transcriptome. Empagliflozin treatment before and after myocardial infarction decreased no reflow and microvascular injury, leading to reduced infiltration of inflammatory cells, reduced infarct size, and improved cardiac function in mice. In diabetic patients receiving empagliflozin after myocardial infarction, perfused boundary region, flow-mediated dilation, and global longitudinal strain were improved.

The influence of the mitochondrial control system on ischemic heart disease has become a major focus of current research. Mitophagy, as a very crucial part of the mitochondrial control system, plays a special role in ischemic heart disease, unlike mitochondrial dynamics. The published reviews have not explored in detail the unique function of mitophagy in ischemic heart disease, therefore, the aim of this paper is to summarize how mitophagy regulates the progression of ischemic heart disease. We conclude that mitophagy affects ischemic heart disease by promoting cardiomyocyte hypertrophy and fibrosis, the progression of oxidative stress, the development of inflammation, and cardiomyocyte death, and that the specific mechanisms of mitophagy are worthy of further investigation.

Increased reactive oxygen species (ROS) are involved in the pathological process of dry eye disease. Our previous results suggested that norepinephrine (NE) has a protective effect on dry eye.

This study explored the potential therapeutic role and underlying mechanisms of NE in benzalkonium chloride (BAC)-induced dry eye disease.

BAC-pretreated human corneal epithelial cells (HCEpiC) were cultured with various concentrations of NE. A BAC-induced dry eye mice model was established to explore the role of NE. Alterations in mice corneal tissues, ROS levels, mitochondrial function, and mitophagy levels were analyzed.

In vitro, our results revealed that BAC-exposed HCEpiC led to mitochondrial malfunction, which involved excessive ROS production, decreased mitochondrial membrane potential (MMP), and promoted mitochondrial fragmentation through increased DRP1 and fission protein 1 (Fis1) expression and reduced mitofusin 2 (Mfn2) expression. Moreover, topical BAC application induced excessive mitophagy. These effects were reversed by NE. Additionally, the increased expression of LC3B, SQSTM1/p62, PINK1, and Parkin, which control mitophagy, in BAC-exposed HCEpiC was suppressed by NE. In BAC-induced C57BL/6J mice, NE resulted in lower fluorescein staining scores, decreased TUNEL-positive cells, and decreased mitochondrial fragmentation.

In conclusion, our findings showed that NE therapy prevented HCEpiC following BAC application by regulating mitochondrial quality control, which is controlled by PINK1/Parkin-dependent mitophagy. Our research suggests a potential targeted treatment for dry eye disease.

Mitophagy is a process in which impaired or dysfunctional mitochondria are selectively eliminated through the autophagy mechanism to maintain mitochondrial quality control and cellular homeostasis. Based on specific target signals, several mitophagy processes have been identified. Defects in mitophagy are associated with various pathological conditions, including neurodegenerative disorders, cardiovascular diseases, metabolic diseases, and cancer. Mitophagy has been shown to play a critical role in the pathogenesis of gynecological malignancies and the development of drug resistance. In this review, we have summarized and discussed the role and recent advances in understanding the therapeutic potential of mitophagy in the development of gynecological malignancies. Therefore, the valuable insights provided in this review may serve as a basis for further studies that contribute to the development of novel treatment strategies and improved patient outcomes.

Gut microflora plays an important role in relieving myocardial no-reflow (NR), formononetin (FMN) has potential effects on NR, however, the relationship between this effect and gut microflora remains unclear. This study aimed to evaluate the role of FMN in alleviating NR by regulating gut microflora. We used a myocardial NR rat model to confirm the effect and mechanism of action of FMN in alleviating NR. The rats were randomly divided into sham operation group (Sham), NR group, FMN group and sodium nitroprusside (SNP) group. Thioflavin S staining, Hematoxylin Eosin (HE), myocardial enzyme activity, ultrasonic cardiogram and RT-PCR detection showed that FMN could effectively reduce inflammatory cell infiltration, NR and ischemic area, improve cardiac structure and function and reduce TNF-α and NF-κB gene expression in NR rats. The results of 16S rRNA high-throughput sequencing showed that FMN could increase the abundance of anti-inflammatory bacteria such as Ligilactobacillus, Coprococcus, Blautia and Muribaculaceae and decrease the abundance of pro-inflammatory bacteria such as Treponema in Spirochaetota and Campylobacterota. The correlation between the differential bacteria in the gut microflora(anti-inflammatory bacteria and pro-inflammatory bacteria) and TNF-α and NF-κB, showed that they had a strong correlation. Therefore, the anti-NR mechanism of FMN may be related to increasing the abundance of anti-inflammatory bacteria and reducing the abundance of pro-inflammatory bacteria to inhibit inflammation. This study provides innovative mechanistic insights into the relationship between gut microbiota and myocardial protection, suggesting potential strategy for future treatment of NR.

The early restoration of hemodynamics/reperfusion in acute myocardial infarction (AMI) is an effective therapeutic strategy to reduce sudden death and improve patient prognosis. However, reperfusion induces additional cardiomyocyte damage and cardiac tissue dysfunction. In this context, turmeric‑derived curcumin (Cur) has been shown to exhibit a protective effect against myocardial ischemia/reperfusion injury (I/RI). The molecular mechanism of its activity, however, remains unclear. The current study investigated the protective effect of Cur and its molecular mechanism via in vitro experiments. The Cell Counting Kit‑8 and lactate dehydrogenase (LDH) assay kit were used to assess the cell viability and cytotoxicity. The contents of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase, glutathione (GSH)/glutathione disulfide (GSSG), total iron, ferrous iron, caspase‑3 and reactive oxygen species (ROS) were measured using an appropriate kit. Western blotting was used to detect the expression of relevant proteins. The levels of apoptosis, mitochondrial permeability transition pore (MPTP) opening, and mitochondrial membrane potential (MMP) were detected by flow cytometry. The study findings indicated that anoxia/reoxygenation (A/R) injury significantly decreased cell viability, increased in LDH and caspase‑3 activities, induced ferroptosis, increased apoptosis and overactivated autophagy. However, pretreatment with Cur or ferrostatin‑1 (Fer‑1, a ferroptosis inhibitor) significantly increased A/R‑reduced cell viability, SOD, glutathione peroxidase activity, GSH/GSSH ratio and HES1 and glutathione peroxidase 4 protein expression; attenuated A/R‑induced LDH, MDA, total iron, ferrous iron, prostaglandin‑endoperoxide synthase 2 protein expression and prevented ROS overproduction and MMP loss. In addition, Cur inhibited caspase‑3 activity, upregulated the Bcl‑2/Bax ratio, reduced apoptotic cell number and inhibited MPTP over‑opening. Furthermore, Cur increased P62, LC3II/I, NDUFB8 and UQCRC2 expression and upregulated the p‑AMPK/AMPK ratio. However, erastin (a ferroptosis activator), pAD/HES1‑short hairpin RNA, rapamycin (an autophagy activator) and Compound C (an AMPK inhibitor) blocked the protective effect of Cur. In conclusion, Cur pretreatment inhibited ferroptosis, autophagy overactivation and oxidative stress; improved mitochondrial dysfunction; maintained energy homeostasis; attenuated apoptosis; and ultimately protected the myocardium from A/R injury via increased HES1 expression.

Venous graft decay (VGD) occurs in coronary artery bypass grafting (CABG), and ischemia-reperfusion oxidative stress injury during the operation is involved in VGD. To explore the cellular phenotypic changes during this process, a stable oxidative stress model of human saphenous vein endothelial cells (HSVECs) is constructed. Through proteomics and cell experiments, it is found that the expression of BCL2L13 is upregulated during oxidative stress of HSVECs, and BCL2L13 regulated mitophagy through receptor-mediated interaction with LC3 and plays a role in cell protection. During oxidative stress, intracellular o8G epigenetic modification occurs, and the o8G modification of miR-6513-5p causes this molecule to lose its targeted regulation of BCL2L13 and participates in the upregulation of BCL2L13. There is a regulatory pathway of o8G modification-BCL2L13-LC3-mitophagy when oxidative stress occurs in HSVECs.

Acute kidney injury (AKI) is associated with a high mortality rate. Pathologically, renal ischemia/reperfusion injury (RIRI) is one of the primary causes of AKI, and hypoxia-inducible factor (HIF)-1α may play a defensive role in RIRI. This study assessed the role of hypoxia-inducible factor 1α (HIF-1α)-mediated mitophagy in protection against RIRI in vitro and in vivo. The human tubular cell line HK-2 was used to assess hypoxia/reoxygenation (H/R)-induced mitophagy through different in vitro assays, including western blotting, immunofluorescence staining, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), and reactive oxygen species (ROS) measurement. Additionally, a rat RIRI model was established for evaluation by renal histopathology, renal Doppler ultrasound, and transmission electron microscopy to confirm the in vitro data. The selective HIF-1α inhibitor LW6 reduced H/R-induced mitophagy but increased H/R-induced apoptosis and ROS production. Moreover, H/R treatment enhanced expression of the FUN14 domain-containing 1 (FUNDC1) protein. Additionally, FUNDC1 overexpression reversed the effects of LW6 on the altered expression of light chain 3 (LC3) BII and voltage-dependent anion channels as well as blocked the effects of HIF-1α inhibition in cells. Pretreatment of the rat RIRI model with roxadustat, a novel oral HIF-1α inhibitor, led to decreased renal injury and apoptosis in vivo. In conclusion, the HIF-1α/FUNDC1 signaling pathway mediates H/R-promoted renal tubular cell mitophagy, whereas inhibition of this signaling pathway protects cells from mitophagy, thus aggravating apoptosis, and ROS production. Accordingly, roxadustat may protect against RIRI-related AKI.

Differentiating dental pulp stem cells (DPSCs) into odontoblasts is a critical process for tooth self-repair and dentine‒pulp engineering strategies in the clinic. However, the mechanism underlying the regulation of DPSC odontoblastic differentiation remains largely unknown. Here, we demonstrated that BCL-2 interacting protein 3 (BNIP3)-dependent mitophagy is associated with importin subunit beta-1 (KPNB1)-activating transcription factor 4 (ATF4), which promotes DPSC odontoblastic differentiation.

The key genes involved in DPSC odontogenic differentiation were identified via bioinformatics. Stable silencing or overexpression of BNIP3 was performed to investigate its impact on DPSC differentiation in vitro (n ≥ 3). To explore the role of BNIP3 in vivo, tooth root fragments loaded with the hydrogel-transfected DPSC complex were implanted into nude mice (n ≥ 6). Dual-luciferase reporter assays and chromatin immunoprecipitation (ChIP) polymerase chain reaction (PCR) were conducted to explore the binding site of ATF4 to the BNIP3 promoter (n ≥ 3). Mitochondrial function experiments were performed to investigate the impact of ATF4-BNIP3 on mitochondria (n ≥ 3). Immunoprecipitation (IP) mass spectrometry (MS) was used to investigate the interaction between ATF4 and its binding protein, KPNB1. Plasmids containing wild-type (WT)/mutant (MUT)-nuclear localization signal (NLS) forms of ATF4 were constructed to determine the specific amino acid residues recognized by KPNB1 and their effects on DPSC odontoblastic differentiation (n ≥ 3).

Compared with those in the control group, the levels of autophagy and mitophagy, especially BNIP3-dependent mitophagy, were greater in the DPSC odontoblastic differentiation group (P < 0.05). Genetic silencing or overexpression of BNIP3 demonstrated that BNIP3 expression was positively correlated with the transition of DPSCs into odontoblasts both in vitro and in vivo (P < 0.05). ATF4 regulates the expression of BNIP3 by directly binding to approximately -1292 to -1279 bp and approximately -1185 to -1172 bp within the BNIP3 promoter region, which is associated with mitophagy and mitochondrial reactive oxygen species (mtROS) levels (P < 0.05). Moreover, ATF4 increased mitophagy, mitochondrial function, and cell differentiation potential via BNIP3 (P < 0.05). Mechanistically, KPNB1 is a novel interacting protein of ATF4 that specifically recognizes amino acids (aa) 280-299 within ATF4 to control its translocation into the nucleus and subsequent transcription and differentiation processes (P < 0.05).

We reported that the critical role of KPNB1/ATF4/BNIP3 axis-dependent mitophagy could provide new cues for the regeneration of the dental pulp‒dentin complex in DPSCs.

Adiponectin receptor 1 ( Adipor1) deficiency has been shown to inhibit Th17 cell differentiation and reduce joint inflammation and bone erosion in antigen-induced arthritis (AIA) mice. Additional emerging evidence indicates that Th17 cells may differentiate into pathogenic (pTh17) and non-pathogenic (npTh17) cells, with the pTh17 cells playing a crucial role in numerous autoimmune and inflammatory conditions. In the current study, we found that Adipor1 deficiency inhibited pTh17 differentiation in vitro and that the deletion of Adipor1 in pTh17 cells reduced the mitochondrial function. RNA-sequencing (RNA-seq) demonstrated a significant increase in the expression levels of Fundc1, a gene related to mitochondrial function, in Adipor1-deficient CD4 + T cells. Interference with the Fundc1 expression in Adipor1-deficient CD4 + T cells partially mitigated the effect of Adipor1 deficiency on mitochondrial function and pTh17 differentiation. In conclusion, the current study demonstrated a novel role of AdipoR1 in regulating mitochondrial function via FUNDC1 to promote pTh17 cell differentiation, providing some insights into potential therapeutic targets for autoimmune and inflammatory diseases.

Sepsis evokes compromised myocardial function prompting heart failure albeit target therapy remains dismal. Our study examined the possible role of mitophagy receptor FUNDC1 in septic cardiomyopathy. A sepsis model was established using cecal ligation and puncture (CLP) in FUNDC1 knockout (FUNDC1-/-) and WT mice prior to the evaluation of cardiac morphology, echocardiographic and cardiomyocyte contractile, oxidative stress, apoptosis, necroptosis, and ferroptosis. RNAseq analysis depicted discrepant patterns in mitophagy, oxidative stress and ferroptosis between CLP-challenged and control murine hearts. Septic patients displayed cardiac injury alongside low plasma FUNDC1 and iron levels. CLP evoked interstitial fibrosis, cardiac dysfunction (lowered ejection fraction, fractional shortening, shortening/relengthening velocity, peak shortening and electrically-stimulated intracellular Ca2+ rise, alongside increased LV end systolic diameter and relengthening duration), O2- buildup, apoptosis, necroptosis, and ferroptosis (downregulated GPX4 and SLC7A11), the responses of which were accentuated by FUNDC1 ablation. In particular, levels of lipid peroxidation enzyme acyl-CoA synthetase long-chain family member 4 (ACSL4) were upregulated following CLP procedure, with a more pronounced response in FUNDC1-/- mice. Co-immunoprecipitation and interaction interface revealed an evident interaction between FUNDC1 and ACSL4. In vitro studies revealed that the endotoxin lipopolysaccharide provoked cardiomyocyte contractile and lipid peroxidation anomalies, the responses were reversed by the mitophagy inducer oleanolic acid, inhibition of ACSL4 and ferroptosis. These findings favor a role for FUNDC1-ACSL4-ferroptosis cascade in septic cardiomyopathy.