Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease worldwide, and its exact pathogenesis has not been fully studied. Hydrogen sulfide (H2S) is the third gas signaling molecule discovered in mammals, following nitric oxide and carbon monoxide. It has the effects of anti-inflammation, anti-apoptosis, and so on, thereby playing an important role in many diseases. However, the role and mechanism of exogenous H2S in NAFLD are not fully understood. In this study, we constructed in vitro and in vivo NAFLD models by feeding mice a high-fat diet and stimulating hepatocytes with palmitic acid, respectively, to investigate the improvement effect and mechanism of exogenous H2S on NAFLD. The results showed that NaHS (a donor of H2S) treatment alleviated lipid accumulation, inflammation, apoptosis and pyroptosis, and downregulated endoplasmic reticulum (ER) stress and nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NRRP3) inflammasome in NAFLD. The activation of NLRP3 inflammasome weakened NaHS improvement of NAFLD, indicating that exogenous H2S ameliorated NAFLD by inhibiting NLRP3 inflammasome-mediated lipid synthesis, inflammation, apoptosis and pyroptosis. Similarly, the activation of ER stress weakened NaHS improvement of NAFLD and NaHS inhibition of NLRP3 inflammasome, indicating that exogenous H2S suppressed NLRP3 inflammasome by downregulating ER stress, thus improving NAFLD. Additionally, the protein expressions of NLRP3 and cleaved caspase-1 were downregulated after inhibiting the reactive oxygen species (ROS)/extracellular signal-regulated kinases (ERK) and ROS/thioredoxin-interacting protein (TXNIP) pathways, indicating that ER stress activated NLRP3 inflammasome through the ROS/ERK and ROS/TXNIP pathways. In conclusion, our results indicated that exogenous H2S inhibited NLRP3 inflammasome-mediated hepatocytes inflammation, lipid synthesis, apoptosis and pyroptosis by downregulating ER stress, thereby improving NAFLD; Furthermore, ER stress activated NLRP3 inflammasome through the ROS/ERK and ROS/TXNIP pathways in NAFLD. ER stress/NLRP3 inflammasome is expected to become a new target of H2S for treating NAFLD.

Diabetic cardiomyopathy (DCM) is a myocardial structural and functional abnormality directly caused by diabetes and is a principal factor in the development of cardiovascular complications in patients with diabetes. The study aims to investigate the role of circOGDH in the development of DCM and elucidate its precise underlying mechanisms. We established two well-characterised diabetic mouse models, C57BL/6J and db/db, and assessed cardiac function by serum lactate dehydrogenase activity assay and echocardiography, as well as quantitative histological analyses of the extent of myocardial fibrosis in combination with HE staining and Masson trichrome staining. The results demonstrated that there was a significant upregulation of circOGDH expression levels in myocardial tissues of mice in a diabetic state, accompanied by increased expression of key effector proteins of PANoptosis. It is noteworthy that the knockdown of circOGDH led to a substantial enhancement in cardiac function indices, a reduction in the area of myocardial fibrosis, and the effective inhibition of the PANoptosis process in myocardial tissues. In the H9c2 cells model, silencing of circOGDH also exhibited significant protective effects, including increased cell survival, reduced levels of oxidative stress, decreased apoptosis, and suppressed expression of PANoptosis-related proteins. Subsequent employing RNA pull-down, RNA immunoprecipitation and co-immunoprecipitation experimental methods have elucidated, for the first time, the molecular mechanism by which circOGDH specifically targets and regulates RIPK3 through the HMGB1 signalling pathway. The present study definitively demonstrated that up-regulation of circOGDH expression in a diabetic state could exacerbate pathological damage in diabetic cardiomyopathy by activating the HMGB1/RIPK3 signalling pathway.

The blood-brain barrier (BBB) serves as a highly selective interface that regulates the transport of molecules between the blood and the brain. Its integrity is essential for maintaining neuronal homeostasis and preventing neuroinflammation. Hyperglycemia, a hallmark of diabetes, is linked to cognitive deficits and central nervous system (CNS) pathologies, including vascular dementia, stroke, and Alzheimer's disease, with BBB damage as a potential contributing factor. As the global prevalence of diabetes rises, understanding the connection between hyperglycemia and BBB dysfunction may facilitate the development of novel treatments that protect or restore BBB integrity, thereby alleviating the neurological complications of diabetes. Furthermore, it may aid in the development of targeted therapies for diabetes-related neurological complications. This literature review examines the emerging insights into the relationship between hyperglycemia and BBB dysfunction. It focuses on the mechanisms underlying BBB dysfunction, the clinical manifestations of this dysfunction in diabetes and cerebrovascular diseases, and potential therapeutic interventions.

Placental angiogenesis is particularly important in the treatment of intrahepatic cholestasis of pregnancy (ICP). Although BACH1 has been implicated in angiogenesis associated with cardiovascular diseases, its specific role and underlying mechanisms in ICP remain unclear. This study aims to investigate the role of BACH1 in ICP.

The study used clinical samples and two distinct mouse models of ICP to validate BACH1 alterations in ICP through immunohistochemistry (IHC), immunofluorescence (IF), and western blot (WB) analyses. Subsequently, global BACH1-knockout mice were employed to investigate the phenotypic effects of BACH1 deficiency on ICP progression. The molecular mechanisms underlying the regulatory role of BACH1 in ICP were further elucidated using multi-omics approaches (e.g., transcriptomics and proteomics), combined with dual-luciferase reporter assays and electrophoretic mobility shift assays (EMSA).

The expression of BACH1 was significantly upregulated in ICP, and its expression level positively correlated with clinicopathological indicators of ICP. Experiments using BACH1-knockout mice demonstrated that BACH1 deletion effectively ameliorated ICP-related placental tissue damage and significantly enhanced the expression levels of angiogenesis markers such as vascular endothelial growth factor (VEGF). Mechanistic investigations indicated that BACH1 deficiency activated the transcriptional expression of solute carrier family 25 member 51 (SLC25A51), thereby promoting the mitochondrial transport of nicotinamide adenine dinucleotide (NAD+), restoring mitochondrial function, and improving the activities of electron transport chain complexes I, II, and IV. Notably, BACH1 deficiency promoted taurocholic acid (TCA)-induced proliferation of human umbilical vein endothelial cells (HUVECs), whereas this phenotype could be reversed by shRNA-mediated knockdown of SLC25A51. Further studies confirmed that administration of the specific BACH1 inhibitor HPPE effectively alleviated TCA-induced suppression of HUVECs proliferation.

BACH1 may suppress placental angiogenesis by inhibiting the transcriptional expression of SLC25A51, making it a potential therapeutic target. Specifically, pharmacological inhibition of BACH1 could provide a targeted therapeutic strategy for placental angiogenesis associated with ICP.

Inflammasomes are multiprotein complexes of the innate immune system that mediate inflammatory responses to infection and to local and systemic stress and tissue injury. The principal function is to facilitate caspase-1 auto-activation and subsequently maturation and release of the effectors interleukin (IL)-1β and IL-18. The atrial-specific NLRP3 inflammasome is a unifying causal feature of atrial fibrillation (AF) development, progression and recurrence after ablation. Many AF-associated risk factors and co-morbidities converge mechanistically on the activation of this central inflammatory signaling platform. This review presents the historical conceptual development of a distinct atrial inflammasome and its potential causal involvement in AF. We follow the early observations linking systemic and local inflammation with AF, to the emergence of an atrial-intrinsic NLRP3 inflammasome operating within not just immune cells but also in resident atrial fibroblasts and cardiomyocytes. We outline the key developments in understanding how the atrial NLRP3 inflammasome and its effector IL-1β contribute causally to cellular and tissue-level arrhythmogenesis in different pathological settings, and outline candidate therapeutic concepts verified in preclinical models of atrial cardiomyopathy and AF.

Heart failure (HF) has emerged as one of the foremost global health threats due to its intricate pathophysiological mechanisms and multifactorial etiology. Adenosine triphosphate (ATP)-induced cell death represents a novel form of regulated cell deaths, marked by cellular energy depletion and metabolic dysregulation stemming from excessive ATP accumulation, identifying its uniqueness compared to other cell death processes modalities such as programmed cell death and necrosis. Growing evidence suggests that ATP-induced cell death (AICD) is predominantly governed by various biological pathways, including energy metabolism, redox homeostasis and intracellular calcium equilibrium. Recent research has shown that AICD is crucial in HF induced by pathological conditions like myocardial infarction, ischemia-reperfusion injury, and chemotherapy. Thus, it is essential to investigate the function of AICD in the pathogenesis of HF, as this may provide a foundation for the development of targeted therapies and novel treatment strategies. This review synthesizes current advancements in understanding the link between AICD and HF, while further elucidating its involvement in cardiac remodeling and HF progression.

Pulmonary fibrosis is a chronic progressive fibrosing interstitial lung disease of unknown cause, characterized by excessive deposition of extracellular matrix, leading to irreversible decline in lung function and ultimately death due to respiratory failure and multiple complications. The Sirtuin family is a group of nicotinamide adenine dinucleotide (NAD+) -dependent histone deacetylases, including SIRT1 to SIRT7. They are involved in various biological processes such as protein synthesis, metabolism, cell stress, inflammation, aging and fibrosis through deacetylation. This article reviews the complex molecular mechanisms of the poorly studied SIRT3, SIRT6, and SIRT7 subtypes in lung fibrosis and the latest research progress in targeting them to treat lung fibrosis.

Necroptosis is a programmed cell death form executed by receptor-interacting protein kinase (RIPK) 1, RIPK3 and mixed lineage kinase domain-like protein (MLKL), which assemble into an oligomer called necrosome. Accumulating evidence reveals that necroptosis participates in many types of pathological processes. Hence, clarifying the mechanism of necroptosis in pathological processes is particularly important for the prevention and treatment of various diseases. For over 300 years, hydrogen sulfide (H2S) has been widely known in the scientific community as a toxic and foul-smelling gas. However, after discovering the important physiological and pathological functions of H2S, human understanding of this small molecule changed, believing that H2S is the third gas signaling molecule after carbon monoxide (CO) and nitric oxide (NO). H2S plays an important role in various diseases, but the related mechanisms are not yet fully understood. In recent years, more and more studies have shown that H2S regulation of necroptosis is involved in various pathological processes. Herein, we focus on the recent progress on the role of H2S regulation of necroptosis in different pathological processes and profoundly analyze the related mechanisms.

HFpEF is a prevalent and complex type of heart failure. The concurrent presence of conditions such as obesity, hypertension, hyperglycemia, and hyperlipidemia significantly increase the risk of developing HFpEF. Mitochondria, often referred to as the powerhouses of the cell, are crucial in maintaining cellular functions, including ATP production, intracellular Ca2+ regulation, reactive oxygen species generation and clearance, and the regulation of apoptosis. Exercise plays a vital role in preserving mitochondrial homeostasis, thereby protecting the cardiovascular system from acute stress, and is a fundamental component in maintaining cardiovascular health. In this study, we review the mitochondrial dysfunction underlying the development and progression of HFpEF. Given the pivotal role of exercise in modulating cardiovascular diseases, we particularly focus on exercise as a potential therapeutic strategy for improving mitochondrial function. Graphical abstract Note: This picture was created with BioRender.com.

The aberrant activation of the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome has been implicated in the exacerbation of myocardial damage and the subsequent development of heart failure following myocardial infarction (MI). Inhibiting NLRP3 inflammasome activation offers a promising therapeutic strategy for mitigating MI-related injury, although no NLRP3 inhibitors have received Food and Drug administration (FDA) approval to date. To identify novel NLRP3 inflammasome inhibitors through the repurposing of FDA-approved drugs, Tamibarotene emerged as a potent inhibitor with a favorable safety profile. Mechanistically, Tamibarotene inhibits NLRP3 inflammasome activation independently of retinoic acid receptor activation, binding to Phe410 and Ile417 within the nucleotide-binding and oligomerization (NACHT) domain in an ATPase activity-dependent manner. This interaction further inhibits the assembly of the NLRP3 inflammasome. In a murine model of MI, Tamibarotene significantly reduced myocardial damage and improved cardiac function by inhibiting NLRP3 inflammasome activation. In summary, NLRP3 has been identified as a direct target of Tamibarotene for myocardial repair following MI, indicating that Tamibarotene could serve as a potential precursor for the development of innovative NLRP3 inhibitors.

Dysregulation of mitochondrial activity is a major cause of diabetes mellitus (DM) and its complications. Astragaloside IV, a natural herbal product, possesses protective properties against DM. This study aimed to evaluate how astragaloside IV affects oxidative stress and mitochondrial function in endothelial progenitor cells (EPCs) and elucidate the underlying mechanisms. A high glucose (HG)-induced human EPC (hEPC) model and a streptozotocin (STZ)-induced DM mouse model were established to investigate the effects of astragaloside IV on EPC function and wound healing in the context of DM. In HG-exposed hEPCs, astragaloside IV reduced apoptosis and increased cell viability and tube formation (P < 0.05). In STZ-induced DM mice, astragaloside IV promoted wound healing and increased the expression of the endothelial marker CD31 (P < 0.05) in wound tissues. In addition, the regulation of oxidative damage and mitochondrial dysfunction by astragaloside IV was investigated. We found that astragaloside IV attenuated mitochondrial damage, decreased ROS and mtROS levels (P < 0.05), decreased MDA activity and enhanced SOD activity (P < 0.05), and downregulated DPR1 levels and upregulated MFN1, MFN2, and OPA1 levels (P < 0.05). Mechanistically, the potential involvement of GSK-3β/Nrf2 was investigated by molecular docking and intervention with the GSK-3β activator sodium nitroprusside (SNP). Astragaloside IV was confirmed to dock with GSK-3β, and it increased the phosphorylation of GSK-3β (P < 0.05) and the expression of Nrf2 as well as its downstream factors HO-1 and NQO1 (P < 0.05). SNP reversed the protective effects of astragaloside IV. These results indicated that astragaloside IV attenuated HG- and STZ-induced injury through the GSK-3β/Nrf2 pathway. These results revealed that astragaloside IV may have the potential to be an active component for protection against DM and its complications.

Chronic ethanol (EtOH) consumption has been widely recognized as a significant contributor to cardiotoxicity. However, no specific treatment is currently available to ameliorate chronic ethanol induced cardiotoxicity. Adiponectin receptor agonist AdipoRon exerts protective effects in multiple organs through alleviating lipotoxicity. Our previous study showed that chronic ethanol consumption increased de novo ceramide synthesis and necroptosis in myocardium. In this study, we investigated the role of AdipoRon on ceramide metabolism and necroptosis in chronic ethanol-treated myocardium. Eight-week-old C57/BL6J mice were fed with a Lieber-Decarli diet containing vehicle or AdipoRon for 12 weeks. Cardiac function, histology and oxidative stress were assessed. We found that chronic ethanol treatment decreased expression of AdipoR2 in myocardium and H9c2 cells, whereas AdipoRon improved cardiac function, reduced myocardium ceramide levels and suppressed necroptosis. By pharmacological interventions, RNA interference and point mutations in AdipoR2, we demonstrated that AdipoRon reduced ceramide levels through PPARα mediated lipid metabolism rather than AdipoR2's ceramidase activity. Using transmission electron microscope and reactive oxygen species (ROS) staining, we showed that chronic ethanol induced myocardium mitochondria damage and mitochondrial reactive oxygen species (mtROS) accumulation. Meanwhile, we found that AdipoRon ameliorated chronic ethanol induced cardiac necroptosis via the SIRT3-SOD2-mtROS pathway. Moreover, C6 ceramide treatment recapitulated chronic ethanol in inducing mtROS and necroptosis, whereas the ceramide synthesis inhibitors myriocin (MYR) and fumonisin B1 (FB1) attenuated chronic ethanol induced mtROS and necroptosis. Collectively, AdipoRon ameliorates chronic ethanol induced cardiac necroptosis by reducing ceramide de novo synthesis and mtROS, which highlights the therapeutic potential of targeting ceramide metabolism and oxidative stress pathways in treating ethanol induced cardiotoxicity.

Energy metabolism is indispensable for sustaining physiological functions in living organisms and assumes a pivotal role across physiological and pathological conditions. This review provides an extensive overview of advancements in energy metabolism research, elucidating critical pathways such as glycolysis, oxidative phosphorylation, fatty acid metabolism, and amino acid metabolism, along with their intricate regulatory mechanisms. The homeostatic balance of these processes is crucial; however, in pathological states such as neurodegenerative diseases, autoimmune disorders, and cancer, extensive metabolic reprogramming occurs, resulting in impaired glucose metabolism and mitochondrial dysfunction, which accelerate disease progression. Recent investigations into key regulatory pathways, including mechanistic target of rapamycin, sirtuins, and adenosine monophosphate-activated protein kinase, have considerably deepened our understanding of metabolic dysregulation and opened new avenues for therapeutic innovation. Emerging technologies, such as fluorescent probes, nano-biomaterials, and metabolomic analyses, promise substantial improvements in diagnostic precision. This review critically examines recent advancements and ongoing challenges in metabolism research, emphasizing its potential for precision diagnostics and personalized therapeutic interventions. Future studies should prioritize unraveling the regulatory mechanisms of energy metabolism and the dynamics of intercellular energy interactions. Integrating cutting-edge gene-editing technologies and multi-omics approaches, the development of multi-target pharmaceuticals in synergy with existing therapies such as immunotherapy and dietary interventions could enhance therapeutic efficacy. Personalized metabolic analysis is indispensable for crafting tailored treatment protocols, ultimately providing more accurate medical solutions for patients. This review aims to deepen the understanding and improve the application of energy metabolism to drive innovative diagnostic and therapeutic strategies.

Lipotoxicity is a significant factor in the pathogenesis of diabetic cardiomyopathy (DbCM), a condition characterized by mitochondrial fragmentation and pyroptosis. Mitochondrial fission protein 1 (FIS1) plays a role in mitochondrial fission by anchoring dynamin-related protein 1 (DRP1). However, the specific contribution of FIS1 to DbCM remains unclear. This study aims to clarify how lipotoxicity-induced upregulation of FIS1 affects mitochondrial fragmentation and the mechanisms linking this fragmentation to NLRP3-dependent pyroptosis in DbCM.

To model lipotoxicity in DbCM, we used db/db mice and primary neonatal rat cardiomyocytes (NRCMs) treated with palmitic acid (PA) and conducted a series of in vivo and in vitro experiments. Gain- and loss-of-function studies on NRCMs were performed using pharmacological inhibitors and small interfering RNA (siRNA) transfection, and we assessed the expression and function of FIS1, mitochondrial dynamics, mitochondrial reactive oxygen species (mitoROS) production, NLRP3-dependent pyroptosis, and their interrelationships.

Our results show that in the myocardium of db/db mice, NLRP3-dependent pyroptosis is associated with upregulation of FIS1, mitochondrial fragmentation, and increased oxidative stress. In NRCMs subjected to PA, the application of VX-765 and MCC950 to inhibit caspase-1 and NLRP3, respectively, significantly reduced pyroptosis. Additionally, pretreatment with Mito-TEMPO (MT) demonstrated that mitoROS are critical initiators for NLRP3 inflammasome activation and subsequent pyroptosis. Furthermore, PA-induced upregulation of FIS1 exacerbates mitochondrial fragmentation. Downregulation of FIS1 or inhibition of FIS1/DRP1 interaction reversed mitochondrial fragmentation, reduced mitoROS levels, and mitigated pyroptosis.

Lipotoxicity-induced FIS1 upregulation exacerbates mitochondrial fragmentation through its interaction with DRP1, leading to increased mitoROS production and the initiation of NLRP3-dependent pyroptosis in DbCM. Therefore, targeting FIS1 emerges as a potential therapeutic approach for managing DbCM.

This study was designed to evaluate the protective effects of eleutheroside B (EB) in high-altitude-induced myocardial injury (HAMI) and to unravel the underlying molecular mechanisms. SD rats were used for in vivo experiments. Following pretreatment with EB, the SD rats were exposed to a hypobaric environment within a hypobaric chamber for 48 h. Electrocardiograms, H&E staining, and serum biochemical indices were measured to evaluate the protective effects of EB on HAMI. Immunofluorescence and Western blotting were utilized to detect the expression of associated proteins. In parallel, a hypobaric hypoxic cell incubator was used to establish an in vitro model of hypobaric hypoxia-induced cell injury. The anti-necroptotic effect and its potential underlying mechanisms were investigated and verified in vitro. Exposure to hypobaric hypoxia led to electrocardiogram disorders, pathological changes in myocardial tissue, increased concentrations of BNP and CK-MB, and elevated levels of oxidative stress indicators and inflammatory factors. Additionally, the expression of necroptosis-related proteins was upregulated. Pretreatment with EB effectively ameliorated myocardial injury caused by hypobaric hypoxia, mitigated oxidative stress and inflammation, and suppressed necroptosis. Furthermore, EB facilitated the translocation of Nrf2 into the nucleus. In conclusion, this study provides evidence suggesting that EB may exert a protective effect against HAMI by inhibiting cardiomyocyte necroptosis via the Nrf2/HO-1 signaling pathway.

Sirtuin-3 (SIRT3) in mitochondria has nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylase activity. As such, SIRT3 is crucial in cardiovascular and neurodegenerative diseases. Advanced proteomics and transcriptomics studies have revealed that SIRT3 expression becomes altered when the heart or brain is affected by external stimuli or disease, such as diabetic cardiomyopathy, atherosclerosis, myocardial infarction, Alzheimer's disease, Huntington's disease, and Parkinson's disease. More specifically, SIRT3 participates in the development of these disorders through its deacetylase activity and in combination with downstream signaling pathways. The paper reviews SIRT3's expression changes, roles, and mechanisms associated with the development of cardiovascular and neurodegenerative diseases. Additionally, strategies targeting SIRT3 to treat or regulate cardiovascular and neurodegenerative disease development are discussed.

Nicotinamide adenine dinucleotide (NAD+) is an essential coenzyme for redox reactions and regulates cellular catabolic pathways. An intertwined relationship exists between NAD+ and mitochondria, with consequences for mitochondrial function. Dysregulation in NAD+ homeostasis can lead to impaired energetics and increased oxidative stress, contributing to the pathogenesis of cardiometabolic diseases. In this review, we explore how disruptions in NAD+ homeostasis impact mitochondrial function in various cardiometabolic diseases. We discuss emerging studies demonstrating that enhancing NAD+ synthesis or inhibiting its consumption can ameliorate complications of this family of pathological conditions. Additionally, we highlight the potential role and therapeutic promise of mitochondrial NAD+ transporters in regulating cellular and mitochondrial NAD+ homeostasis.

Diabetic cardiomyopathy, characterized by myocardial fibrosis, is a common complication of diabetes. Retinoic acid-related orphan receptor α (RORα) participates in various pathological and physiological cardiovascular processes. The current research aims to elucidate the roles and mechanisms of RORα in high glucose induced cardiac fibroblasts proliferation. Primary neonatal cardiac fibroblasts were isolated from Sprague-Dawley rats, and pre-administrated with RORα antagonist SR3335 (20 µM) or RORα agonist SR1078 (10 µM) followed by the stimulation with normal glucose (5.5 mM) or high glucose (33.3 mM) respectively. Lactate Dehydrogenase (LDH) release into culture medium, cellular adenosine-triphosphate (ATP), and cell number were detected. Expressions of Collagen I, Collagen III, proliferating cell nuclear antigen (PCNA), α-smooth muscle actin (α-SMA), receptor-interacting protein kinase 1 (RIPK1) and receptor-interacting protein kinase 3 (RIPK3) were evaluated. The extent of oxidative stress was also assessed. Our study found that high glucose elevated LDH release, reduced cellular ATP production, increased cells numbers, elevated expression of Collagen I, Collagen III, PCNA, α-SMA, RIPK1 and RIPK3, decreased mitochondrial membrane potential, strengthened intensity of dihydroethidium (DHE) and MitoSOX fluorescence. Above effects were all further exacerbated by SR3335 but significantly reversed by SR1078. In conclusion, RORα antagonist SR3335 promoted cell injury and proliferation, enhanced collagen synthesis, facilitated oxidative stress and necroptosis in cardiac fibroblasts with high glucose stimulation, whereas RORα agonist SR1078 showed opposing effects. Our study proposed RORα as a novel target against high glucose-induced cardiac fibroblasts proliferation, which is beneficial to clarify ideal therapeutic implication for diabetic cardiomyopathy.

It is well-established that chronic hyperglycemia progressively destroys the heart structure, weakening function and leading to diabetic cardiomyopathy (DCM). Extracellular vesicles derived from adipose-derived stem cell (ADSC-EVs) have been reported to have anti-inflammatory and immune-modulating effects, but their role in DCM is still poorly understood. Therefore, this study investigated the impact of ADSC-EVs on DCM and potential mechanisms. ADSC-EVs were isolated from the conditioned media of ADSCs. DCM rat models were established using streptozotocin (STZ) in vivo, and high glucose (HG) stimulated H9c2 cardiomyocytes to establish in vitro model. Then mRNA sequencing identified Chit1 as a key gene. Both in vivo and in vitro experiments demonstrated that chitinase 1 (Chit1) and NLRP3/Caspase-1-mediated pyroptosis levels were significantly upregulated in myocardial tissue of rat diabetic cardiomyopathy and hyperglycemic cardiomyocytes, which was reversed by ADSC-EVs treatment. We next observed that in hyperglycemic cardiomyocytes, downregulating Chit1 also resulted in a decrease in NLRP3/Caspase-1-mediated pyroptosis proteins. To a certain extent, the inhibitory effect of ADSC-EVs on the NLRP3/Caspase-1 signaling pathway was reversed by Chit1 overexpression. Taken together, we identified a novel mechanism by which ADSC-EVs regulate NLRP3/Caspase-1-mediated pyroptosis through Chit1 to alleviate diabetic cardiomyopathy, offering an innovative strategy for DCM treatment.

Subarachnoid hemorrhage (SAH) is a type of hemorrhagic stroke, and the neuroprotective effects of nimodipine following SAH have been well-documented. Sirtuin 3 (SIRT3), a mitochondrial nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase, plays a significant role in mitigating oxidative stress in various neurodegenerative conditions. However, the role of SIRT3 in the neuroprotective mechanisms of nimodipine after SAH remains unclear. In this study, the in vitro cytotoxicity of neurons exposed to 2% ethanol (to stimulate oxidative stress) was assessed. An in vivo experimental SAH model was established in adult mice through internal carotid perforation. A series of in vitro and in vivo experiments were conducted to investigate the function of SIRT3 and its potential mechanisms in nimodipine-treated SAH. Nimodipine, at a concentration of 10 μM within 48 h of incubation, exerted significant neuroprotective effects, enhancing SIRT3 protein expression under oxidative stress. Functional in vitro studies revealed that elevated SIRT3 expression improved mitochondrial function and promoted neuronal autophagy. Additional studies unveiled that SIRT3 knockdown or inhibition of autophagosome formation using inhibitor 3-methyladenine suppressed nimodipine-induced autophagy. The absence of autophagy increased neuronal cytotoxicity and mitochondrial dysfunction, decreased the release of anti-inflammatory cytokines, and increased the release of proinflammatory cytokines. Furthermore, blocking autophagy exacerbated neuronal apoptosis worsened neurological outcomes, and nullified the neuroprotective effects of nimodipine in the SAH mouse model. These findings highlight a mechanism where SIRT3 mediates nimodipine's neuroprotective effects by regulating mitochondrial function and autophagy. This suggests that SIRT3 serves as a promising therapeutic target for SAH.

Protein lactylation is a new form of post-translational modification that has recently been proposed. Lactoyl groups, derived mainly from the glycolytic product lactate, have been linked to protein lactylation in brain tissue, which has been shown to correlate with increased neuronal excitability. Ischemic stroke may promote neuronal glycolysis, leading to lactate accumulation in brain tissue. This accumulation of lactate accumulation may heighten neuronal excitability by upregulating protein lactylation levels, potentially triggering post-stroke epilepsy. Although current clinical treatments for seizures have advanced significantly, approximately 30% of patients with epilepsy remain unresponsive to medication, and the prevalence of epilepsy continues to rise. This study explores the mechanisms of epilepsy-associated neuronal death mediated by lactate metabolism and protein lactylation. This study also examines the potential for histone deacetylase inhibitors to alleviate seizures by modifying lactylation levels, thereby offering fresh perspectives for future research into the pathogenesis and clinical treatment of epilepsy.

Approximately one-tenth of the global population is affected by diabetes mellitus, and its incidence continues to rise each year. In China, 1.4 million patients die from diabetes-related complications every year. Additionally, approximately 26% of patients with diabetes develop diabetic cardiomyopathy, with heart failure being one of the main causes of death in these patients. However, early detection of diabetic cardiomyopathy has proven to be difficult in a clinical setting; furthermore, there are limited guidelines and targeted means of prevention and treatment for this disease. In recent years, several studies have provided evidence for the occurrence of various forms of regulated cell death in diabetic myocardial cells, including apoptosis, necroptosis, ferroptosis, and cuproptosis, which are closely linked to the pathological progression of diabetic cardiomyopathy. Although most research on diabetic cardiomyopathy is currently in the animal trial phase, the inhibition of these regulatory cell death processes can limit or slow down the progression of diabetic cardiomyopathy. Therefore, this review discusses the appropriate animal experimental models currently available for diabetic cardiomyopathy and evaluates the roles of apoptosis, necroptosis, ferroptosis, and cuproptosis in diabetic cardiomyopathy. We hope to provide new methods and ideas for future research in diabetic cardiomyopathy.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) exert cardiovascular benefits in diabetic patients, but the underlying mechanisms remain incompletely understood. Semaglutide, a novel long-acting GLP-1RA, has shown a reduced risk of cardiovascular events. Based on these results, we investigated the therapeutic potential of semaglutide in diabetic cardiomyopathy and sought to elucidate the underlying mechanisms.

Mice with diabetes induced by high-fat diet/streptozotocin were treated with semaglutide. The mechanisms underlying the cardioprotective effects of semaglutide were analysed using animal and cell experiments.

In diabetic mice, semaglutide alleviated metabolic disorders, ameliorated myocardial fibrosis, improved cardiac function, antagonized oxidative stress and suppressed cardiomyocyte apoptosis. More significantly, semaglutide attenuated cardiac inflammation through restoring Raf kinase inhibitor protein (RKIP) expression and inhibiting downstream TANK-binding kinase 1 (TBK1)-NF-κB pathway. Meanwhile, decreased RKIP expression and activated TBK1-NF-κB signalling pathway were also found in tissues from human diabetic hearts. RKIP deficiency exacerbated cardiac inflammation and offset the cardioprotective effect of semaglutide in diabetic mice. Moreover, semaglutide also restored the expression level of Sirtuin 3(Sirt3), which served as a modulator against cardiac inflammation by regulating RKIP-dependent pathway. In diabetic mice, RKIP deficiency abolished the cardioprotective benefits conferred by the Sirt3 activator honokiol. We also found that cAMP/PKA signalling, rather than glucose lowering, contributed to the anti-inflammatory effect of semaglutide through Sirt3-dependent RKIP pathway.

Semaglutide exerted cardioprotective effects against diabetic heart failure by alleviating cardiac inflammation through Sirt3-dependent RKIP signalling pathway.

Cellular senescence is a state of permanent cell cycle arrest and plays an important role in many vascular lesions. This study found that the cells of diabetic patients have more characteristics of senescence, which may cause microvascular complications. Cell senescence, as one of the common fates of cells, links microangiopathy and diabetes. Cell senescence in a high-glucose environment can partially elucidate the mechanism of diabetic microangiopathy, and various types of cellular senescence induced by it can promote the progression of diabetic microangiopathy. Still, the molecular mechanism of microangiopathy-related cellular senescence has not yet been clearly studied. Building on recent research evidence, we herein summarize the fundamental mechanisms underlying the development of cellular senescence in various microangiopathies associated with diabetes. We gradually explain how cellular senescence serves as a key driver of diabetic microangiopathy. At the same time, the treatment of basic senescence mechanisms such as cellular senescence may have a great impact on the pathogenesis of the disease, may be more effective in preventing the development of diabetic microangiopathy, and may provide new ideas for the clinical treatment and prognosis of diabetic microangiopathy.

Photodynamic therapy and ferroptosis induction have risen as vanguard oncological interventions, distinguished by their precision and ability to target vulnerabilities in cancer cells. Photodynamic therapy's non-invasive profile and selective cytotoxicity complement ferroptosis' unique mode of action, which exploits iron-dependent lipid peroxidation, offering a pathway to overcome chemoresistance with lower systemic impact. The synergism between photodynamic therapy and ferroptosis is underscored by the depletion of glutathione and glutathione peroxidase four inhibitions by photodynamic therapy-induced reactive oxygen species, amplifying lipid peroxidation and enhancing ferroptotic cell death. This synergy presents an opportunity to refine cancer treatment by modulating redox homeostasis. Porphyrin-based nanoscale metal-organic frameworks have unique hybrid structures and exceptional properties. These frameworks can serve as a platform for integrating photodynamic therapy and ferroptosis through carefully designed structures and functions. These nanostructures can be engineered to deliver multiple therapeutic modalities simultaneously, marking a pivotal advance in multimodal cancer therapy. This review synthesizes recent progress in porphyrin-modified nanoscale metal-organic frameworks for combined photodynamic therapy and ferroptosis, delineating the mechanisms that underlie their synergistic effects in a multimodal context. It underscores the potential of porphyrin-based nanoscale metal-organic frameworks as advanced nanocarriers in oncology, propelling the field toward more efficacious and tailored cancer treatments.

Mitochondrial dysfunction and oxidative stress play important roles in diabetic retinal vascular injuries. Honokiol (HKL) is a small-molecule polyphenol that exhibits antioxidant effects and has a beneficial effect in diabetes. This study aimed to explore the potential ability of HKL to ameliorate vascular injury in diabetic retinopathy (DR) and its possible mechanisms of action.

The effect of HKL was evaluated in vascular injury in an in vivo type 2 diabetic (db/db) mouse model. In vitro, retinal microvascular endothelial cells were treated with high glucose (HG) to simulate the pathological diabetic environment. Cell viability, expression of apoptosis-related proteins, cellular reactive oxygen species, mitochondrial membrane potential, and morphological changes in the mitochondria were examined.

The diabetic mice exhibited severe retinal vascular damage, including vascular leakage in vivo and capillary endothelial cell apoptosis in vitro. HKL reversed the retinal vascular leakage in the diabetic mice. In vitro, HKL improved retinal capillary endothelial cell viability, decreased apoptosis, and reversed the HG-induced increased cellular oxidative stress and mitochondrial fragmentation. The sirtuin 3 (SIRT3) inhibitor 3-TYP blocked all the in vivo and in vitro protective effects of HKL against diabetic retinal vascular leakage and capillary endothelium and eliminated the decrease in oxidative stress levels and reduction of mitochondrial fragmentation.

In conclusion, these findings suggest that HKL inhibits vascular injury in DR, which was likely achieved through SIRT3-mediated mitochondrial fusion. This study provides a potential new strategy for the treatment of DR.

Ozone (O 3), a prevalent atmospheric pollutant, can induce lung injury. However, the molecular mechanisms of O 3-induced acute lung inflammatory injury remain unclear. In this study, we investigate the abnormal changes in and molecular mechanism of mitochondrial homeostasis in alveolar macrophages (AMs) in O 3-induced acute lung inflammatory injury mice. Mitochondria and mitochondrial reactive oxygen species (mtROS) are labeled with Mito-Tracker® Deep Red and MitoSOX Red, respectively. Mitochondrial DNA (mtDNA) in AMs from the bronchoalveolar lavage fluid (BALF) is detected via real-time PCR, and the expressions of mitochondrial fusion/fission-related and biogenesis-related proteins in AMs are determined via immunofluorescence staining. Our data show that in O 3-induced acute lung inflammatory injury mice, the number of AMs and the protein expression of the NLRP3 inflammasome complex in the lung tissue are increased. In AMs from O 3-exposed mice, the number of mitochondria, mtROS, and fission-related protein DRP1 are increased, but the levels of Na +-K +-ATPase, fusion-related protein OPA1, biogenesis-related protein NRF1 and mtDNA are significantly decreased. Compared with that in O 3-exposed WT mice, lung inflammation is attenuated, especially the indicators of mitochondrial homeostatic imbalance in AMs, which are alleviated in NLRP3 ‒/‒ and Caspase-1 ‒/‒ mice after O 3 exposure. These findings indicate that the NLRP3 inflammasome-mediated imbalance in mitochondrial homeostasis in AMs contributes to O 3-induced acute lung inflammatory injury. This study may provide a new target for the prevention of lung inflammation induced by O 3.

Antimony (Sb) is a metalloid, widely presents in the environment and associates with human health. In this study, we aimed to decipher whether Sb exposure is harmful to female reproduction and explore the underlying mechanisms. The ICR mice were exposed to 0, 5, 10, and 20 mg/kg acetate potassium Sb tartrate trihydrate by intraperitoneal injection for 10 days, then mouse oocytes were collected for further analysis. We first found a significant decrease in the proportion of MII-stage oocytes obtained from supernumerary ovulation in the fallopian tubes and early embryo development under Sb treatment. Then a series of tests showed Sb affects oocyte maturation by damaging the cytoskeleton of microtubule and actin. Moreover, the abnormal distribution of cortical granules and their component Ovastacin in oocytes, combined with reduced expression levels of Juno, affected sperm-oocyte binding and led to fertilization failure. Based on the sequencing results and experimental validation, it was demonstrated that Sb exposure impairs mitochondrial distribution and membrane potential, elevated levels of mitochondrial superoxide, finally caused energy supply deficits. Mitochondrial damage in oocytes after Sb exposure results in the excessive oxidative stress and early apoptosis. Taken together, these data suggest that Sb exposure decreases oocyte quality and female fertilization ability by impairing mitochondrial function and redox perturbation.

Diabetic cardiomyopathy (DCM), a complication of diabetes, poses a significant threat to public health, both its diagnosis and treatment presents challenges. Teneligliptin has promising applications and research implications in the treatment of diabetes mellitus. Zhang et al observed the therapeutic effect of teneligliptin on cardiac function in mice with DCM. They validated that teneligliptin's mechanism of action in treating DCM involves cardiomyocyte protection and inhibition of NLRP3 inflammasome activity. Given that the NLRP3 inflammasome plays a crucial role in the onset and progression of DCM, it presents a promising therapeutic target. Nevertheless, further clinical validation is required to ascertain the preventive and therapeutic efficacy of teneligliptin in DCM.

Cell death constitutes a critical component of the pathophysiology of cardiovascular diseases. A growing array of non-apoptotic forms of regulated cell death (RCD)-such as necroptosis, ferroptosis, pyroptosis, and cuproptosis-has been identified and is intimately linked to various cardiovascular conditions. These forms of RCD are governed by genetically programmed mechanisms within the cell, with epigenetic modifications being a common and crucial regulatory method. Such modifications include DNA methylation, RNA methylation, histone methylation, histone acetylation, and non-coding RNAs. This review recaps the roles of DNA methylation, RNA methylation, histone modifications, and non-coding RNAs in cardiovascular diseases, as well as the mechanisms by which epigenetic modifications regulate key proteins involved in cell death. Furthermore, we systematically catalog the existing epigenetic pharmacological agents targeting novel forms of RCD and their mechanisms of action in cardiovascular diseases. This article aims to underscore the pivotal role of epigenetic modifications in precisely regulating specific pathways of novel RCD in cardiovascular diseases, thus offering potential new therapeutic avenues that may prove more effective and safer than traditional treatments.

PIWI-interacting RNAs (piRNAs) are involved in the regulation of hypertrophic cardiomyopathy, heart failure and myocardial methylation. However, their functions and the underlying molecular mechanisms in diabetic cardiomyopathy (DCM) have yet to be fully elucidated. In the present study, a pyroptosis-associated piRNA (piR112710) was identified that ameliorates cardiac remodeling through targeting the activation of inflammasomes and mitochondrial dysfunction that are mediated via the thioredoxin-interacting protein (Txnip)/NLRP3 signaling axis. Subsequently, the cardioprotective effects of piR112710 on both the myocardium from db/db mice and cardiomyocytes from neonatal mice that were incubated with a high concentration of glucose combined with palmitate were examined. piR112710 was found to significantly improve cardiac dysfunction in db/db mice, characterized by improved echocardiography, lower levels of fibrosis, attenuated expression levels of inflammatory factors and pyroptosis-associated proteins (namely, Txnip, ASC, NLRP3, caspase-1 and GSDMD-N), and enhanced myocardial mitochondrial respiratory functions. In cultured neonatal mice cardiomyocytes, piR112710 deficiency and high glucose along with palmitate treatment led to significantly upregulated expression levels of pyroptosis associated proteins and collagens, oxidative stress, mitochondrial dysfunction and increased levels of inflammatory factors. Supplementation with piR112710, however, led to a reversal of the aforementioned changes induced by high glucose and palmitate. Mechanistically, the cardioprotective effect of piR112710 appears to be dependent upon effective elimination of reactive oxygen species and inactivation of the Txnip/NLRP3 signaling axis. Taken together, the findings of the present study have revealed that the piRNA-mediated inhibitory mechanism involving the Txnip/NLRP3 axis may participate in the regulation of pyroptosis, which protects against DCM both in vivo and in vitro. piR112710 may therefore be a potential therapeutic target for the reduction of myocardial injury caused by cardiomyocyte pyroptosis in DCM.

The field of reproductive biology has made significant progress in recent years, identifying specific molecular players that influence oocyte development and function. Among them, sirtuin 3 (SIRT3) has attracted particular attention for its central role in mediating mitochondrial function and cellular stress responses in oocytes. So far, studies have demonstrated that the knockdown of SIRT3 leads to a decrease in blastocyst formation and an increase in oxidative stress within an embryo, underscoring the importance of SIRT3 in maintaining the cellular redox balance critical for embryonic survival and growth. Furthermore, the literature reveals specific signaling pathways, such as the SIRT3- Glycogen synthase kinase-3 beta (GSK3β) deacetylation pathway, crucial for mitigating oxidative stress-related anomalies in oocyte meiosis, particularly under conditions like maternal diabetes. Overall, the emerging role of SIRT3 in regulating oocyte mitochondrial function and development highlights the critical importance of understanding the intricate connections between cellular metabolism, stress response pathways, and overall reproductive health and function. This knowledge could lead to the development of novel strategies to support oocyte quality and fertility, with far-reaching implications for assisted reproductive technologies and women's healthcare. This commentary aims to provide an overview of the importance of SIRT3 in oocytes by synthesizing results from a multitude of studies. The aim is to elucidate the role of SIRT3 in oocyte development, maturation, and aging and to identify areas where further research is needed.

Maintaining metabolic homeostasis is crucial for cellular and organismal health throughout their lifespans. The intricate link between metabolism and inflammation through immunometabolism is pivotal in maintaining overall health and disease progression. The multifactorial nature of metabolic and inflammatory processes makes study of the relationship between them challenging. Homologs of Saccharomyces cerevisiae silent information regulator 2 protein, known as Sirtuins (SIRTs), have been demonstrated to promote longevity in various organisms. As nicotinamide adenine dinucleotide-dependent deacetylases, members of the Sirtuin family (SIRT1-7) regulate energy metabolism and inflammation. In this review, we provide an extensive analysis of SIRTs involved in regulating key metabolic pathways, including glucose, lipid, and amino acid metabolism. Furthermore, we systematically describe how the SIRTs influence inflammatory responses by modulating metabolic pathways, as well as inflammatory cells, mediators, and pathways. Current research findings on the preferential roles of different SIRTs in metabolic disorders and inflammation underscore the potential of SIRTs as viable pharmacological and therapeutic targets. Future research should focus on the development of promising compounds that target SIRTs, with the aim of enhancing their anti-inflammatory activity by influencing metabolic pathways within inflammatory cells.

Heart failure with preserved ejection fraction (HFpEF) is a condition that develops in the course of many diseases and conditions, and its pathophysiology is still not well understood, but the involvement of programmed types of cell death in the development of this type of heart failure is becoming increasingly certain. In addition, drugs already widely used in clinical practice, with a good safety profile and efficacy demonstrated in large-group clinical trials, seem to be exerting their beneficial effects on cardiovascular health. Perhaps new drugs that reduce the susceptibility of cells to programmed types of cell death are under investigation and may improve the prognosis of patients with HFpEF. In this article, we summarize the current knowledge about the pathogenesis of HFpEF and the role of programmed types of cell death in its development. Additionally, we have described the future directions of research that may lead to the improvement of a patient's prognosis and potential treatment.

Diabetic cardiomyopathy (DCM) represents one of the typical complications associated with diabetes. It has been described as anomalies in heart function and structure, with consequent high morbidity and mortality. DCM development can be described by two stages; the first is characterized by left ventricular hypertrophy and diastolic dysfunction, and the second by heart failure (HF) with systolic dysfunction. The proposed mechanisms involve cardiac inflammation, advanced glycation end products (AGEs) and angiotensin II. Furthermore, different studies have focused their attention on cardiomyocyte death through the different mechanisms of programmed cell death, such as apoptosis, autophagy, necrosis, pyroptosis and ferroptosis. Exosome release, adipose epicardial tissue and aquaporins affect DCM development. This review will focus on the description of the mechanisms involved in DCM progression and development.

Mitochondria are responsible for maintaining cellular energy levels, and play a major role in regulating homeostasis, which ensures physiological function from the molecular to whole animal. Sirtuin 3 (SIRT3) is the major protein deacetylase of mitochondria. SIRT3 serves as a nutrient sensor; under conditions of mild metabolic stress, SIRT3 activity is increased. Within the mitochondria, SIRT3 regulates every complex of the electron transport chain, the tricarboxylic acid (TCA) and urea cycles, as well as the mitochondria membrane potential, and other free radical scavengers. This article reviews the role of SIRT3 in regulating homeostasis, and thus physiological function. We discuss the role of SIRT3 in regulating reactive oxygen species (ROS), ATP, immunological function and mitochondria dynamics.

PANoptosis is a unique innate immune inflammatory lytic cell death pathway initiated by an innate immune sensor and driven by caspases and RIPKs. As a distinct pathway, the execution of PANoptosis cannot be hindered by targeting other cell death pathways, such as pyroptosis, apoptosis, or necroptosis. Instead, targeting key PANoptosome components can serve as a strategy to prevent this form of cell death. Given the physiological relevance in several diseases, PANoptosis is a pivotal therapeutic target. Notably, previous research has primarily focused on the role of PANoptosis in cancer and infectious and inflammatory diseases. By contrast, its role in cardiovascular diseases has not been comprehensively discussed. Here, we review the available evidence on PANoptosis in cardiovascular diseases, including cardiomyopathy, atherosclerosis, myocardial infarction, myocarditis, and aortic aneurysm and dissection, and explore a variety of agents that target PANoptosis, with the overarching goal of providing a novel complementary approach to combatting cardiovascular diseases.

Given the heightened risk of diabetes-related cardiovascular events associated with inactivity, this study investigates the molecular mechanisms of vascular damage in streptozotocin (STZ)-induced diabetic rats. The aim is to elucidate the impact of different exercises (interval and continuous training) and metformin on biochemical parameters, aortic injury, oxidative stress, and inflammation to provide insights into potential therapeutic interventions for diabetes-associated vascular complications. Male Wistar rats were administered a single dose of STZ (60 mg/kg) to induce diabetes. Diabetic rats underwent either interval training or continuous training (40 min/day, 5 days/week, 6 weeks), received metformin (300 mg/kg), or a combination of metformin and exercise. After 6 weeks, biochemical parameters in serum and oxidative stress markers and mRNA expression of endothelial nitric oxide synthase (eNOS), lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), and intercellular adhesion molecule-1 (ICAM-1) in aorta tissue were assessed. Serum levels of fasting blood sugar (FBS), triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL), TG/HDL, TC/HDL, and LDL/HDL ratios were significantly reduced in all treatment groups compared to the diabetes group. Both types of exercises, metformin, and exercise+metformin combinations, significantly reduced oxidative stress by decreasing malondialdehyde (MDA) and enhancing the antioxidant status in the aortic tissue compared to the diabetic group. In addition, in exercise groups, metformin, and combination groups, the expression of eNOS was significantly elevated, while LOX-1 and ICAM-1 expression significantly decreased compared to the diabetic group. In most cases, the combination of exercise and metformin (especially interval training) was more effective than exercise alone. It seems that exercise along with taking metformin can be considered as a therapeutic method by improving hyperglycemia and hyperlipidemia and reducing oxidative stress and vascular inflammatory responses, leading to ameliorating biomarkers function related to endothelial damage in experimental diabetes conditions.

Septic myocardial injury is a common complication of severe sepsis, which occurs in about 50% of cases. Patients with this disease may experience varying degrees of myocardial damage. Annexin-A1 short peptide (ANXA1sp), with a molecular structure of Ac-Gln-Ala-Tyr, has been reported to exert an organ protective effect in the perioperative period by modulating sirtuin-3 (SIRT3). Whether it possesses protective activity against sepsis-induced cardiomyopathy is worthy of study. This study aimed to investigate whether ANXA1sp exerts its anti-apoptotic effect in septic myocardial injury in vitro and in vivo via regulating SIRT3. In this study, we established in vivo and in vivo models of septic myocardial injury based on C57BL/6 mice and primary cardiomyocytes by lipopolysaccharide (LPS) induction. Results showed that ANXA1sp pretreatment enhanced the seven-day survival rate, improved left ventricular ejection fraction (EF), left ventricular fractional shortening (FS), and cardiac output (CO), and reduced the levels of creatine kinase-MB (CK-MB), cardiac troponin I (cTnI), and lactate dehydrogenase (LDH). Western blotting results revealed that ANXA1sp significantly increased the expression of SIRT3, Bcl-2, and downregulated Bax expression. TUNEL staining and flow cytometry results showed that ANXA1sp could attenuate the apoptosis rate of cardiomyocytes, whereas this anti-apoptotic effect was significantly attenuated after SIRT3 knockout. To sum up, ANXA1sp can alleviate LPS-induced myocardial injury by reducing myocardial apoptosis via SIRT3 upregulation.