Lysine lactylation is a recently discovered post-translational modification with broad implications in cancer biology. Emerging evidence indicates that the canonical alanyl-tRNA synthetase (AARS1) also functions as a lactyltransferase. Notably, lysine lactylation catalyzed by AARS1 has been implicated in cancer progression. Recent findings elucidate the mechanism by which lactate transitions from a metabolic byproduct to a signaling molecule, highlighting AARS1’s central role in metabolic reprogramming, tumor progression, and immune regulation. A deeper understanding of AARS1-mediated lactylation substrates, regulatory networks, and functional variations across tissues and disease states will provide new insights for developing precision interventions targeting lactylation pathways. This review integrates emerging evidence on AARS1 as a lactyltransferase, assessing its clinical implications and proposing therapeutic strategies for AARS1-associated cancers.

Atopic dermatitis (AD) is a highly heterogeneous chronic inflammatory skin disease, and the exact role and mechanisms of interleukin (IL)-19 in AD remain unclear. This study integrated serum samples from AD patients, transcriptomic data from clinical AD lesions, AD-like mouse models with exogenous IL-19 supplementation or IL-19 gene knockout, and in vitro cellular models to investigate its mechanism of action. Serum IL-19 levels correlated with disease severity after adjustment for clinical covariates and type 2 cytokines in this cohort. In an MC903-induced AD-like mouse model, exogenous IL-19 supplementation exacerbated the dermatitis phenotype, whereas IL-19 gene knockout alleviated it. Mechanistically, keratinocytes constituted the primary source of IL-19 within AD lesions, with house dust mites inducing its upregulation in these cells in vitro. IL-19 acted through the STAT6/STAT3 signaling pathway to suppress loricrin and keratin-10 expression, which may result in epidermal barrier impairment. Simultaneously, it upregulated thymic stromal lymphopoietin and IL-33, potentially facilitating the type 2 inflammatory cascade in AD. Furthermore, IL-19 may additively exacerbate inflammatory responses with IL-13 and IL-4. Collectively, these findings support a role for IL-19 as a pro-inflammatory mediator in AD, suggesting that IL-19 contributes to both epidermal barrier dysfunction and type 2 immune dysregulation in this disease.

Hepatocellular carcinoma (HCC), the most prevalent type of liver cancer globally, imposes a heavy burden on global public health owing to its consistently high incidence and mortality rates. Owing to the characteristics of its tissue structure, HCC has a high propensity for metastasis. Unfortunately, most patients are diagnosed at the middle or advanced stage and present with metastasis. The occurrence of metastasis often indicates a severe deterioration of the condition and the loss of an opportunity for radical treatment. Thus, immunotherapy represented by immune checkpoint inhibitors (ICIs) has become the first-line treatment for patients with advanced metastasis. The tumor immune microenvironment (TIME), as the core immune component within tumors, has been confirmed to be significantly associated with metastasis through the complex crosstalk with suppressive immune cells. This crosstalk dynamically participates in the metastatic cascade of HCC, assisting tumors in completing invasion and diffusion. The goal of immunotherapy is to restore the function of exhausted immune cells in the TIME. However, the complex immunosuppressive microenvironment often weakens treatment responses, posing severe challenges to the application of immunotherapies. Accordingly, there is an urgent need to deeply investigate the crosstalk among diverse cell types within the immunosuppressive microenvironment and to systematically elucidate the impact of such intercellular crosstalk on the HCC metastasis as well as the response to immunotherapy, so as to improve the clinical benefit rate of immunotherapy for patients with metastatic HCC. This review focuses on the dual role of immune cells in HCC metastasis and the novel mechanisms by which they promote the HCC metastatic cascade. It systematically summarizes current therapeutic strategies targeting the immunosuppressive microenvironment to combat HCC metastasis. On this basis, it prospectively proposes the future development direction of immunotherapy, providing more effective guidance for the clinical diagnosis and treatment of patients with metastatic HCC.

Solid tumors induce systemic immune suppression, including impaired B lymphopoiesis in the bone marrow (BM). This study elucidates a novel mechanism by which remote tumors disrupt early B cell development. We demonstrate that tumor-bearing hosts exhibit skewed BM hematopoiesis favoring myeloid lineages at the expense of lymphoid lineages, specifically B cells. This impairment originates at the Common Lymphoid Progenitors (CLPs) stage. Mechanistically, monocytes, particularly CXCR2⁺ monocytes within the BM of tumor bearing mice leads to significantly elevated secretion of inflammatory cytokines TNF-α and IL-1β. These cytokines suppress CLPs differentiation into B cells. Furthermore, the enhanced secretion of TNF-α and IL-1β is mainly amplified by elevated levels of myeloid-derived S100A8/A9 proteins in the tumor-bearing BM microenvironment. Collectively, these findings identify the S100A8/A9 / TNF-α/IL-1β axis as a critical pathway disrupting B lymphopoiesis in cancer, revealing potential therapeutic targets to restore immune competence and improve immunotherapy responses.

Interleukin-6 (IL-6) plays a pivotal role in the pathogenesis of cancer cachexia (CC). Our prior work showed that L-carnitine (LC) ameliorates skeletal muscle atrophy in TNF-α-induced cachectic models, but its effects on IL-6-induced wasting remain unclear. This study investigated LC’s efficacy against IL-6-induced CC-related atrophy and identified possible mechanisms. In vitro, LC concentration-dependently reversed IL-6-induced C2C12 myotube atrophy and restored cell viability. In female murine models of CC, LC increased the gastrocnemius cross-sectional area by 28.70% (P<0.05) and tumor-free body weight by 32.37% (P<0.05) compared with the MC38 group, and improved the lean mass and muscle function and reduced the serum IL-6 level. Mechanistically, LC downregulated IL-6 and atrophy-associated proteins (MuRF1, Atrogin-1), inhibited FOXO1 activity and AMPK phosphorylation, and promoted mTOR phosphorylation. Together, these findings suggest that LC alleviates IL-6-associated muscle atrophy in female mice, although its efficacy in male subjects warrants further investigation. The present work suggests that LC potentially ameliorates CC via a mechanism involving modulation of the AMPK/mTOR and AMPK/FOXO1 signaling axes, highlighting its possible therapeutic potential for CC.

Due to a lack of complete mechanistic understanding, there are no specific therapeutics for necrotizing enterocolitis (NEC), a deadly gastrointestinal disease affecting premature newborns. While sodium butyrate offers intestinal protection, its efficacy is strictly dose-dependent, and the underlying mechanisms regulating intestinal epithelial cell (IEC) survival remain elusive. Here, using neonatal murine NEC models and human IECs, we demonstrate that moderate-dose butyrate (50 mg/kg) significantly attenuates mucosal injury and improves survival, whereas high-dose butyrate (250 mg/kg) exacerbates mortality by inducing complex cell death pathways including necroptosis and ferroptosis. Mechanistically, moderate butyrate suppresses glycolysis and intracellular lactate production, which restores expression of the translational regulator PABPC1; PABPC1 then binds to YB-1 mRNA to enhance YB-1 protein synthesis without altering transcription. Elevated YB-1 subsequently binds BCL-2 mRNA, increasing BCL-2 protein levels to inhibit intrinsic mitochondrial apoptosis. Functional validation shows that YB-1 knockdown abolishes butyrate-mediated protection and exacerbates TNF-α-induced apoptosis, while YB-1 overexpression rescues cell viability, and exogenous lactate supplementation reverses these effects by suppressing the PABPC1-YB-1 axis. These findings elucidate a novel Lactate-PABPC1-YB-1-BCL-2 signaling axis through which butyrate safeguards the intestinal epithelium, highlighting precise dosing and the modulation of epithelial translational control as promising therapeutic strategies for NEC.

Intracerebral hemorrhage (ICH) often has a poor prognosis, necessitating the exploration of effective therapeutic targets. Stromal interaction molecule 1 (STIM1) is a crucial regulator of cellular calcium homeostasis, but its specific role in ICH remains unclear. This study finds consistent elevation of STIM1 in neurons after ICH, with increased plasma levels in patients correlating with poor prognosis. Neuronal knockout of STIM1 in mice improves brain tissue damage and neurological injury. Mechanistically, STIM1 exacerbates neuronal injury primarily by promoting ferroptosis. Importantly, in addition to regulating calcium signaling pathways, STIM1 directly regulates iron homeostasis through its interaction with transferrin receptor 1 (TFR1) to promote ferroptosis. Finally, through virtual screening, S-IN-1 is identified as an inhibitor targeting STIM1-TFR1 interaction, protecting against neuronal ferroptosis and brain injury. These findings confirm the molecular function of STIM1 in regulating iron homeostasis, providing valuable insights and promising targets for ICH treatment.

Triple-negative breast cancer (TNBC) remains a challenging and clinically aggressive subtype due to its heterogeneity and high mortality rate. Recent molecular subtyping has identified distinct TNBC subgroups with varying therapeutic responses, highlighting the need for targeted therapeutic strategies. The mesenchymal (MES) subtype is characterized by low immune cell infiltration, cancer stem cell-like features, and resistance to multiple drugs. Ferroptosis, a form of iron-dependent cell death, has emerged as a promising therapeutic strategy in TNBC due to the abundance of iron and lipids in tumor cells. However, ferroptosis sensitivity varies across different TNBC subtypes. Notably, the MES subtype exhibits resistance to ferroptosis despite elevated iron levels, due to impaired ferroptosis-executing mechanisms. This study investigates the role of SLC22A3, an organic cation transporter, which is enriched in MES tumors and positively correlates with markers of tumor stem cells. High SLC22A3 expression in MES-TNBC cells modulates serotonin uptake and metabolism, conferring ferroptosis resistance through two pathways. First, 5-HT(serotonin) acts as a radical-trapping antioxidant, eliminating lipid peroxides and inhibiting ferroptosis. Second, 5-HT induces histone serotonylation, which enhances histone methylation and facilitates the recognition of methylated histones by transcriptional initiation factors. This process activates SIRT1 transcription, inhibiting MAOA transcription mediated by FOXO1, thereby reducing 5-HT degradation and promoting ferroptosis resistance. Moreover, we identified potential SLC22A3 inhibitors and their synergistic combinations with ferroptosis inducers or cisplatin, which suppress tumor growth in both MES-subtype TNBC patient-derived organoids and in vivo, offering a promising strategy for personalized therapy. These findings suggest that targeting SLC22A3, along with ferroptosis inducers, may offer a promising therapeutic strategy for patients with MES-subtype TNBC.SLC22A3 affects serotonin uptake and metabolism in MES-TNBC cells, providing ferroptosis resistance through two mechanisms. 5-HT acts as a radical-trapping antioxidant, eliminating lipid peroxides and inhibiting ferroptosis. In addition, 5-HT induces histone serotonylation, which enhances histone methylation and facilitates the recognition of methylated histones by transcription initiation factors. This process activates SIRT1 transcription, inhibiting MAOA transcription mediated by FOXO1, thereby reducing 5-HT degradation and promoting ferroptosis resistance. TKIs served as SLC22A3 inhibitors and their combinations with RSL3 or cisplatin, which inhibit tumor growth in vivo, offering new personalized treatment options for MES-TNBC patients.

Obesity remains a worldwide health issue, with visceral adipose tissue as a leading driver of this pathology. As the executors of biological functions in living cells, proteins have their activity regulated by diverse post-translational modifications, including ubiquitination. However, obesity-related changes in ubiquitination of visceral adipose tissue (VAT) proteins are still poorly understood. Here, we obtained the global proteomic and ubiquitylomic data of epididymal VAT from lean and obese male mice by mass spectrometry. Our proteomic analyses revealed significant changes of metabolic pathways involved in fatty acid, acyl-CoA and branched chain amino acids metabolism in obese VAT. Intriguingly, a comparative analysis of proteomic and ubiquitylomic data highlighted discordance in the quantity changes of certain proteins and their ubiquitination levels. Notably, STEAP4 exhibited a markedly reduced protein level coupled with an enhanced K48-linked ubiquitination, suggesting a potential role for ubiquitination-mediated proteasome degradation in VAT dysfunction. Further in vitro experiments revealed that knockdown of STEAP4 in adipocytes impaired mitochondrial function of 3T3-L1 adipocytes. Collectively, this study introduces the first combined proteomic and ubiquitylomic examination of murine VAT, offering novel insights and potential therapeutic targets for obesity.

The OP9 culture system is an important in vitro model for B cell development. However, the complex nature of operations and the intrinsic variability of stromal cell functionality, which can be influenced by factors such as radiation exposure or contamination, pose considerable challenges to their wider application. Currently, there exists a paucity of studies documenting in vitro B cell differentiation culture systems that exclude stromal cells, and the experimental methodologies available for reference remain limited. This report elucidates a robust stromal cell-free culture system. Specifically, bovine serum albumin (BSA) or fetal bovine serum (FBS), in conjunction with interleukin-7 (IL-7), Flt3 ligand (Flt3L), and stem cell factor (SCF), were incorporated into X-VIVO15 medium. This system proficiently facilitates the directed differentiation of common lymphoid progenitor cells (CLP), defined as lineage-CD127 + CD117lowsca-1lowCD135+, into B lymphocytes in vitro, achieving an amplification factor of up to one hundredfold. We examined the roles of IL-7, Flt3L and SCF in differentiation of B cells from CLP in this culture system. Our findings indicate that IL-7 is a pivotal cytokine essential for B cell differentiation in vitro, demonstrating a notable synergistic impact when combined with SCF and FLT3L. Moreover, this system is capable of supporting the differentiation of hematopoietic stem cells (HSCs) and lymphoid-primed multipotent progenitor cells (LMPPs) into B cells in vitro. The findings substantiated the efficacy of the culture system in investigating the in vitro differentiation of bone marrow-derived progenitor cells into B cells and elucidated the specific roles of BSA, FBS and three cytokines (IL-7, FLT3L and SCF) in promoting efficient B lineage differentiation.

Heat stress (HS) is known to cause liver injury through mechanisms involving oxidative stress and inflammation, thereby highlighting the need for effective therapeutic interventions. This study evaluated the efficacy of sprouted black quinoa extract (SBQE) in mitigating HS-induced liver injury in a rat model. SBQE was obtained through an ultrasonication-assisted ethanol–water extraction process from black quinoa germinated for 48 h. Sprague Dawley rats (male) were administered via oral gavage SBQE at doses of 200, 400, or 800 mg/kg prior to each HS exposure (40 °C for 2 h per day over a period of 8 days). Pretreatment with SBQE resulted in a dose-dependent reduction in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, with the high dose (800 mg/kg) reducing these enzyme levels (p < 0.001 vs. HS group) and alleviating histopathological damage, including a significant decrease in hepatocyte vacuolization and inflammatory cell infiltration (histopathological scores were reduced by p < 0.001 in the 800 mg/kg SBQE group vs. HS group). SBQE also dose-dependently inhibited the accumulation of mitochondrial reactive oxygen species (mean fluorescence intensity decreased by p < 0.001 at 800 mg/kg) and the formation of malondialdehyde while restoring the activities of antioxidant enzymes such as superoxide dismutase (p < 0.01 at 800 mg/kg), catalase (p < 0.05 at 800 mg/kg), and glutathione peroxidase (p < 0.001 at 800 mg/kg), as well as replenishing glutathione levels (p < 0.001 at 800 mg/kg). Furthermore, the levels of proinflammatory cytokines (tumor necrosis factor-alpha, interleukin-6, interleukin-1β, and interleukin-18) in liver tissue were significantly reduced (with the high dose leading to p < 0.001 vs. HS group), which was associated with enhanced nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2; p < 0.05 at 800 mg/kg) and decreased phosphorylation of nuclear factor-κB p65 (NF-κB; p < 0.001 at 800 mg/kg). Additionally, the protein expression of NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome components and markers of apoptosis were diminished. The results demonstrated that SBQE alleviated HS-induced liver injury by concurrently activating the Nrf2 antioxidant pathway and suppressing NF-κB/NLRP3 inflammasome signaling, suggesting its potential as a nutraceutical intervention for HS-related hepatotoxicity.

Exposure of PM2.5 can cause different degrees of lung injury, which is referred with inflammatory response. Some evidences showed that low-dose radiation (LDR) induces hormesis in immune, however, it is unknown if LDR ameliorates the PM2.5-induced lung injury. Additionally, gut microbiota and inflammation are crucial in lung injury and the health benefits of LDR through gut microbiota need further exploration. Here, we aim to investigate the impact of LDR on PM2.5-induced lung injury in vivo and in vitro, and elucidated the potential mechanisms of anti-inflammation activated by gut microbiota. We observed that LDR ameliorated the lung damage induced by PM2.5 in mice. Additionally, after PM2.5 exposure, M1 polarization of macrophages in alveolar lavage fluid and Th1 polarization in spleen increased, pro-inflammatory cytokines (IL-1, IL-6 and TNF-α) increased and anti-inflammatory cytokines (IL-4, IL-10 and TGF-β) decreased in lung and serum. LDR could deteriorate the changes described as above. Intriguingly, Akkermansia muciniphila (Akk) differed most significantly in the gut microbiota of mice. Notably, PM2.5 activated the Toll-like receptors-induced MyD88/NF-κB pathways to mediate the pro-inflammation, and LDR could inhibited the pathway. However, the TLR1 and TLR2 continuously increased after LDR, indicating the downstream non-canonical TLR1/TLR2 pathway of Akk was activated to blunt the pro-inflammation of PM2.5. Our results strongly indicate that LDR-induced activation of gut Akk-dependent non-canonical TLR1/TLR2-like receptor pathway ameliorates lung injury and inflammation resulted from PM2.5.

Increasing evidence demonstrates a close relationship between daily diet and homeostasis of the body’s internal environment, particularly hematopoietic system homeostasis. Hematopoietic stem cells (HSCs) are located at the top of the hematopoietic system and have the ability to self-renew and differentiate into various types of immune cells. They play an important role in maintaining body stability and health. Studies have shown that different diets can lead to changes in HSC homeostasis, thereby affecting immune function and overall health status of the body. However, there is a scarcity of comprehensive reviews on how different diets affects HSC function. Therefore, this review summarizes the current progression in research on the effects of a high-fat diet (HFD) and energy-restricted diet on HSC function. HFD has a predominantly negative effect on HSCs, as does severe energy-restricted diet (SERD). Conversely, moderate energy-restricted diet (dietary restriction, DR) promotes the repopulation of HSCs but seriously impairs the differentiation of HSCs into lymphoid lineage. Further study of the influence of different diets on HSCs may aid in designing rational dietary guidelines to optimize the hematopoietic and immune functions of the body, which has significant implications for clinical medical practices.

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease with complex pathogenesis. This study integrated bioinformatics and experimental validation to elucidate the molecular pathways and discover novel therapeutic targets for AD diagnostic and treatment. Methods: Transcriptomic datasets GSE182740 (training cohort, n = 75) and GSE5667 (validation cohort, n = 34) were analyzed. DEGs identified via GEO2R (|logFC|>2, p < 0.01) underwent KEGG/GO enrichment (Metascape; min overlap = 3, p < 0.01). STRING-constructed PPI networks (interaction score>0.4) visualized in Cytoscape (v3.10.1) revealed top 5 hub genes by CytoHubba MCC scoring. Immune cell infiltration patterns were quantified using ssGSEA software, with in vitro validation conducted in TNF-α/IFN-γ-stimulated keratinocytes. Results: Among 979 significant DEGs, inflammation-related pathways (IL-17, TNF-α, PI3K-Akt, p < 0.05) were enriched. PPI analysis revealed five cell cycle-regulating hub genes (AURKA, BUB1B, CCNB1, MELK, and TTK), all upregulated in AD lesions. In vitro experiments confirmed the upregulation of these hub genes in AD. These genes correlated significantly with activated CD4 T cells, Th2 cells, Treg cells, and central memory CD8 T cells (p < 0.05). In vitro experiments confirmed the overexpression of five hub genes in keratinocytes induced by inflammatory factors. Conclusion: This study identified five hub genes driving AD by disrupting keratinocytes cell cycle regulation. These genes mediated keratinocytes-immune interactions, providing novel targets for AD therapy.

Chronic inflammation in adipose tissue is widely recognized as a pivotal link connecting obesity to a spectrum of related chronic diseases, including type 2 diabetes, non-alcoholic fatty liver disease, and cardiovascular disorders. In this pathogenic process, the dysregulated interaction between adipocytes and adipose-resident immune cells plays a critical regulatory role; however, the underlying mechanisms governing this abnormal interaction remain largely unknown. In this study, we showed that upregulated β2-microglobulin expression in hypertrophic adipocytes during obesity not only mediated the activation of adipose-resident CD8+ T cells in a cell contact-dependent manner but also facilitated iron overload and the ferroptosis of adipocytes, thereby promoting the M1 polarization of adipose tissue macrophages. Conversely, specific ablation of β2-microglobulin in adipocytes effectively suppressed the activation and accumulation of adipose-resident CD8+ T cells, as well as adipocyte ferroptosis and M1 polarization, ultimately preventing high-fat diet-induced obesity and its related inflammation and metabolic disorders. Additionally, adeno-associated virus-mediated adipose-targeted knockdown of β2-microglobulin has been demonstrated to therapeutically alleviate high-fat diet-induced obesity, as well as its related chronic inflammation and metabolic disorders. Furthermore, our bioinformatic analysis of human adipose transcriptome data revealed a strong correlation between adipose β2-microglobulin and obesity. More importantly, β2-microglobulin is significantly upregulated in adipocytes isolated from patients with obesity. Thus, our findings highlight the pivotal role of adipocytes in obesity-associated chronic inflammation and metabolic disorders via β2-microglobulin-dependent mechanisms.

Autoreactive CD8+ T cells play a key role in type 1 diabetes (T1D), but the antigen spectrum that activates autoreactive CD8+ T cells remains unclear. Endoplasmic reticulum stress (ERS) has been implicated in β-cell autoantigen generation. Here, we analyzed the major histocompatibility complex class I (MHC-I)-associated immunopeptidome (MIP) of islet β-cells under steady and ERS conditions and found that ERS reshaped the MIP of β-cells and promoted the MHC-I presentation of a panel of conventional self-peptides. Among them, OTUB258-66 showed immunodominance, and the corresponding autoreactive CD8+ T cells were diabetogenic in nonobese diabetic (NOD) mice. High glucose intake upregulated pancreatic OTUB2 expression and amplified the OTUB258-66-specific CD8+ T-cell response in NOD mice. Repeated OTUB258-66 administration significantly reduced the incidence of T1D in NOD mice. Interestingly, peripheral blood mononuclear cells (PBMCs) from patients with T1D, but not from healthy controls, showed a positive IFN-γ response to human OTUB2 peptides. This study provides not only a new explanation for the role of ERS in promoting β-cell-targeted autoimmunity but also a potential target for the prevention and treatment of T1D. The data are available via ProteomeXchange with the identifier PXD041227.

Shockwave-induced traumatic brain injury (TBI) results in the onset of post-traumatic stress disorder (PTSD), triggered either by the TBI itself or other stressors. However, the interplay and underlying mechanisms of how these factors synergistically induce PTSD remain inadequately elucidated. Here, mice in the TBI (induced by biological shock tube blast injury) and PTSD (induced by single prolonged stress method) groups both displayed symptoms of PTSD behaviors, with the TBI+PTSD (composite model) group exhibiting more severe manifestations. The result of snRNA-seq demonstrated a noticeable increase in the population of Gabra6+ neurons in the prefrontal cortex region of mice in the TBI+PTSD group. Knocking down cortical Gabra6 mitigated PTSD-related behavioral outcomes. Mechanistically, the Smad3/4 complex activation led to the upregulation of Gabra6 expression in cortical neurons. Interaction of Gabra6 with Homer1 activated downstream cAMP signaling pathways. Homer1KO-Nestin mice show reduced susceptibility to PTSD. Subsequently, the efficacy of monoclonal antibody intervention at the 218 site of Gabra6 in ameliorating PTSD development is verified. This study suggests that TBI and stressors act as independent components in PTSD development, with Gabra6+ neurons pivotal in synergistically facilitating PTSD formation. Strategies geared toward minimizing exposure to singular or combined stressors may effectively diminish the risk of developing PTSD.

Nonalcoholic steatohepatitis (NASH) is a metabolism -associated fatty liver disease with accumulated mitochondrial stress, and targeting mitochondrial function is a potential therapy. The mitochondrial genome-encoded bioactive peptide MOTS -c plays broad physiological roles, but its effectiveness and direct targets in NASH treatment are still unclear. Here, we show that long-term preventive and short-term therapeutic effects of MOTS -c treatments alleviate NASH-diet-induced liver steatosis, cellular apoptosis, inflammation, and fibrosis. Mitochondrial oxidative capacity and metabolites profiling analysis show that MOTS -c significantly reverses NASH-induced mitochondrial metabolic deficiency. Moreover, we identify that MOTS -c directly interacts with the BH3 domain of antiapoptotic B cell lymphoma -2 (Bcl-2), increases Bcl-2 protein stability, and suppresses Bcl-2 ubiquitination. By using a Bcl-2 inhibitor or adeno-associated virus (AAV)-mediated Bcl-2 knockdown, we further confirm that MOTS -c improves NASH-induced mitochondrial dysfunction, inflammation, and fibrosis, which are dependent on Bcl-2 function. Therefore, our findings show that MOTS -c is a potential therapeutic agent to inhibit the progression of NASH.