BACKGROUND:An overdose of acetaminophen (APAP) can cause severe liver injury and may even lead to death. However, the mechanisms that underlie APAP-induced liver injury (AILI) are not fully understood. The extensive liver necrosis resulting from APAP overdose aggravates the sterile inflammatory response by activating resident macrophages and recruiting various immune cells. Numerous studies have highlighted the crucial role of lipid metabolism in macrophage function. This study investigated fatty acid metabolism in hepatic macrophages and its impact on the progression of AILI. METHODS:We administered APAP intraperitoneally to C57/B6L mice to induce acute liver injury and studied lipid changes in hepatic macrophages. We treated hepacytes with APAP and collected the conditioned medium to stimulate macrophages. Moreover, we generated a myeloid-specific knockout of Fasn mice to validate the role of de novo lipogenesis in macrophages during AILI. RESULTS:We stained liver tissue sections with Bodipy493/503 lipid dye and observed elevated lipid levels in hepatic macrophages after AILI. Mechanistically, HMGB1 released from necrotic hepatocytes increases FASN expression by activating the PI3K/AKT/sterol regulatory element-binding protein-1 (SREBP1) signaling pathway in macrophages. The enhanced de novo lipogenesis increased inflammatory factor expression in macrophages and facilitated their migratory ability. Conversely, myeloid-specific knockout of Fasn reduced the inflammatory response of macrophages and inhibited their chemotaxis in vivo and in vitro. Furthermore, either myeloid-specific knockout of Fasn or treatment with orlistat, a FASN inhibitor, notably improved liver necrosis and accelerated injury resolution following AILI in mice. CONCLUSIONS:Our findings suggest that targeting de novo lipogenesis in hepatic macrophages may represent a novel strategy for treating AILI.

Post-traumatic stress disorder (PTSD) is increasingly recognized as a brain-body disorder in which excessive retention of pathological fear memory coincides with profound cardiac autonomic dysregulation, substantially elevating cardiovascular morbidity, including the risk of myocardial infarction. Despite this dual burden, therapeutic strategies capable of concurrently rescuing the core persistent fear memory retention deficits and normalizing stress-induced cardiac autonomic dysfunction remain critically lacking. Here, using a single prolonged stress-induced rat model of PTSD, we found that intranasal oxytocin (OXT) administration not only alleviates pathological over-retention of fear memory but also rescues fear cue-elicited abnormalities in heart rate and heart rate variability. Crucially, cervical vagotomy abolished these cardioprotective effects, indicating that OXT’s cardiac regulatory actions rely on an intact vagus nerve pathway to re-establish cardiac autonomic homeostasis. Furthermore, in vivo electrophysiological recordings revealed that intranasal OXT robustly activates ventral tegmental area (VTA) dopamine (DA) neurons, elevating both the firing and burst rates. Immunofluorescence staining further confirms abundant OXT receptor expression within these DA neurons. Collectively, these results uncover a coordinated central-peripheral regulatory cascade modulated by intranasal OXT that mitigates PTSD-associated behavioral and physiological deficits, with VTA dopaminergic signaling likely serving as a major upstream mediator.

Nanoparticle-protein corona interactions critically determine biological responses but remain poorly characterized in living systems due to the lack of noninvasive analytical tools. In this study, we developed a redox-omics strategy that facilitated the in situ mapping of corona composition by tracking cysteine thiol oxidation markers induced by nanoparticles. As a research tool, we synthesized natural-organic-matter-derived carbon dots (nCDs) with dual superoxide dismutase/catalase-mimetic activity. A global redox-omics analysis identified 104 proteins that demonstrated significant redox reactions in response to treatment with nCDs. In particular, we found that nCDs specifically induced a conformational change in isocitrate dehydrogenase 1 (IDH1) by selectively reversing the oxidation of cysteine 269 (Cys269). In the mechanism, the site-specific reduction in cysteine 269 (Cys269) triggered a conformational switch of IDH1 that restored mitochondrial α-ketoglutarate flux and NADPH homeostasis, thereby blocking cytosolic mitochondrial DNA (mtDNA) leakage and subsequent cGAS-STING-driven neuroinflammation. Crucially, the nCDs-mediated metabolic checkpoint control inhibited the pro-inflammatory (M1) phenotypes of microglia, thereby achieving therapeutic efficacy in both zebrafish and murine ischemic stroke models, without inducing detectable toxicity. Collectively, we developed a label-free platform enabling in situ decoding of protein corona interactions via redox-sensitive cysteine profiling, eliminating the need for nanoparticle surface modifications.

Mesenchymal stromal cells (MSCs) hold significant promise in regenerative medicine, yet their clinical application is hindered by challenges such as cellular heterogeneity and quality control. This study aims to develop a rapid, noninvasive method for evaluating the quality of MSCs using femtosecond laser label-free imaging (FLI). We examined the proliferation, metabolic dynamics, and differentiation potential of MSCs from various tissue sources, including human dental pulp, umbilical cord, and fat, across different passages. Conventional experiments show that as the number of passages increases, the morphology of MSCs alters, proliferation capacity decreases, β-galactosidase activity linked to aging rises, and both osteogenic and adipogenic differentiation abilities markedly decline. FLI technology effectively captures these changes: reduced NAD(P)H/FAD ratio in higher-passage cells suggests decreased metabolic activity, while enhanced aging-related fluorescence signals, such as lipofuscin, align with cellular senescence. In the assessment of differentiation capability, increased fluorescence intensity of NAD(P)H and FAD signals indicates heightened metabolic activity within the cells. With the passages increasing, the fluorescence intensities of NAD(P)H and FAD decline, suggesting diminished ability of cell differentiation. Furthermore, during osteogenic differentiation, the optical REDOX ratio (FAD/(NAD(P)H + FAD)) decreases with successive passages, whereas during adipogenic differentiation, it increases. Three-dimensional FLI of suspension cells further reveals that the cells of lower-passage exhibit greater spatial heterogeneity in metabolic signals, possibly reflecting more active mitochondrial function. This study demonstrates that FLI technology can effectively assess the proliferation activity, senescence, and differentiation potential of MSCs through noninvasive, dynamic monitoring of their metabolic status and morphological features, offering a novel approach for standardized quality assessment of MSCs preparations.

Excessive visceral fat is an essential risk factor of metabolic dysfunction-associated steatotic liver disease (MASLD). Yet, the cellular and molecular mechanisms implicated in the correlation between visceral fat metabolism and hepatic steatosis remain poorly understood. Here we report post-expansive epididymal adipose tissue (EAT) atrophy and hepatic steatosis in mice fed a high-fat diet (HFD) primarily due to elevated adipocyte lipolysis in EAT. Mast cell (MC) accumulation in EAT represents a lipolysis-associated feature. Pharmacological stabilization of MCs suppresses EAT adipocyte lipolysis, and improves EAT atrophy and hepatic steatosis. MC-derived serotonin (5-HT) correlates with visceral adipose tissue (VAT) lipolysis in HFD-fed mice as well as in MASLD patients. Conditional deletion of 5-HT from MCs or its receptor HTR2b on adipocytes demonstrates that MC-derived 5-HT promotes adipocyte lipolysis, EAT atrophy, and hepatic steatosis by binding on adipocyte HTR2b. These results suggest that MCs and MC-derived 5-HT are potential therapeutic targets for obesity-associated MASLD. ### Competing Interest Statement The authors have declared no competing interest. the National Natural Science Foundation of China, 32070757, 32200630 the Fundamental Research Funds for the Central Universities, PA2025GDGP0026, JZ2024HGTB0242

Abnormal mechanical stress is closely linked to intervertebral disc degeneration (IVDD). Iron homeostasis disorder occurs in various degenerative diseases, including IVDD. PIEZO1 serves as a mechanosensitive cation channel, involving in multiple physiological and pathological processes; however, its potential association with iron homeostasis and IVDD remain to be elucidated. Here, it is discovered that PIEZO1 accumulates in cartilage endplate (CEP) during IVDD, accompanied by intensive ferritinophagy. Specific activation of PIEZO1 or NCOA4 (nuclear receptor coactivator 4) aggravates CEP degeneration. Conversely, chondrocyte-specific knockout of Piezo1 mitigates CEP degeneration by restoring the labile iron pool and stabilizing the mitochondrial genome. Mechanistically, PIEZO1-mediated nuclear translocation of YAP1 (Yes1 associated transcriptional regulator) enhances NCOA4-dependent ferritinophagy by promoting extracellular Ca2+ influx under oxidative stress. Moreover, ferritinophagy induces in the accumulation and release of Z-form mitochondrial DNA (Z-mtDNA), resulting in the activation of ZBP1 (Z-DNA binding protein 1), ultimately leading to NFKB-dependent inflammatory cascade. Therapeutically, blocking PIEZO1-mediated calcium influx or suppressing YAP1 activation alleviates ferritinophagy. Additionally, Ncoa4 silencing attenuates Z-mtDNA-ZBP1-NFKB axis-driven IVDD. Collectively, our findings suggest that mechanical overload induces ferritinophagy-dependent CEP degeneration via PIEZO1 activation and subsequent upregulation of the Z-mtDNA-ZBP1-NFKB axis, which might furnish a therapeutic target for IVDD.Abbreviation: AAV: adeno-associated virus; ALP: alkaline phosphatase; ARS: alizarin red S; BV:TV: bone volume:total volume; CAMK2/CaMKII: calcium/calmodulin dependent protein kinase II; CEP: cartilage endplate; CEPCs: cartilage endplate chondrocytes; ChIP: chromatin immunoprecipitation; CKO: conditional knockout; CsA: cyclosporin A; Co-IP: co-immunoprecipitation; DHI: disc height index; ECM: extracellular matrix; EtBr: ethidium bromide; HIF: hypoxia inducible factor; IVDD: intervertebral disc degeneration; KD: knockdown; LAT: large tumor suppressor kinase; LSI: lumbar spine instability; MDA: malondialdehyde; Mito-ROS: mitochondrial reactive oxygen species; MRI: magnetic resonance imaging; mtDNA: mitochondrial DNA; NCOA4: nuclear receptor coactivator 4; PCBP: poly(rC) binding protein; ROS: reactive oxygen species; RT-qPCR: real-time quantitative reverse transcription; SOFG: safranin O and fast green; WWTR1/TAZ: WW domain containing transcription regulator 1; TEAD1: TEA domain transcription factor 1; TEM: transmission electron microscopy; YAP1: Yes1 associated transcriptional regulator; ZBP1: Z-DNA binding protein 1; Z-DNA: Z-form DNA; Z-mtDNA: Z-form mitochondrial DNA.

Atherosclerosis (AS), a leading cause of cardiovascular disease (CVD), is closely associated with excessive oxidative stress. Dietary nitrate has emerged as a promising intervention for cardiovascular protection through the nitrate-nitrite-nitric oxide (NO) pathway. Meanwhile, dental pulp stem cell (DPSC) possess potent antioxidant properties. However, the potential synergistic effect of sodium nitrate (NaNO3) and DPSC on AS remains unclear. In this study, ApoE(-/-) mice were fed a high-fat diet (HFD) and treated with NaNO3 and/or DPSC. The combined treatment markedly attenuated atherosclerotic plaque formation, reduced oxidative stress, increased endothelial NO synthase (eNOS) expression, and decreased circulating monocyte levels. Furthermore, in vitro assays revealed that NaNO3 and DPSC synergistically alleviated oxidative stress and promoted macrophage polarization toward the M2 phenotype, thereby suppressing oxidized lipid uptake. Mechanistic studies revealed that these benefits were mediated by activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway and the subsequent upregulation of heme oxygenase-1 (HO-1). Collectively, our findings unveil a novel therapeutic strategy that combines NaNO3 with DPSC to alleviate oxidative stress and inflammation, presenting a promising approach for the treatment of AS.

Hepatic fibrosis, driven by chronic liver injury, results from complex interactions between hepatocytes and hepatic stellate cells (HSCs). In response to hepatocyte damage, activated HSCs undergo transdifferentiation into myofibroblast-like cells, contributing to the accumulation of extracellular matrix (ECM) components and the progression of fibrosis. This review explores the intricate bidirectional crosstalk between hepatocytes and HSCs, focusing on the molecular mechanisms underlying their interactions during liver fibrosis. Hepatocytes, upon injury, release inflammatory mediators, reactive oxygen species (ROS), and exosomes, which activate HSCs and promote fibrotic progression. Conversely, activated HSCs exacerbate hepatocyte dysfunction through cytokine release, ECM remodeling, and mechanical stress. Key signaling pathways, including transforming growth factor-beta (TGF-β), platelet-derived growth factor (PDGF), and oxidative stress mechanisms, are central to these processes. The review also discusses current challenges in targeting hepatic fibrosis and proposes future research directions, including the use of multi-omics technologies to unravel the dynamic spatiotemporal interactions between hepatocytes and HSCs. Understanding this intricate regulatory network will be crucial for the development of novel therapeutic strategies to reverse liver fibrosis and improve patient outcomes.

OBJECTIVES:This prospective study aimed to develop and validate integrated nomograms that combine preoperative radiomic features from dual-layer spectral detector CT (DLCT) with key postoperative pathological information for the prediction of programmed cell death ligand 1 (PD-L1) expression in invasive lung adenocarcinoma. METHODS:The study included 191 participants with invasive lung adenocarcinoma who underwent preoperative thoracic contrast-enhanced DLCT scans and PD-L1 expression testing. Radiomic features were extracted from various DLCT images. Least absolute shrinkage and selection operator was used to derive radscores for PD-L1 expression (tumor proportion score ≥1% was defined as PD-L1 positivity). Nomograms were developed by integrating radscores with clinicopathological characteristics through logistic regression analysis. Performance was assessed using receiver operator characteristic (ROC) curves, area under the curve (AUC), calibration curves, and decision curve analysis (DCA). RESULTS:Three sets of radiomic nomograms, based on iodine map (IM), virtual non-contrast (VNC), and conventional images (PCI), along with pathological stages (pTNM), were developed. The IM nomogram exhibited superior performance in both training (AUC = 0.791) and validation (AUC = 0.737) sets. Calibration and DCA confirmed the IM nomogram's consistency and clinical utility. CONCLUSIONS:The IM nomogram demonstrated potential for individualized prediction of PD-L1 expression in invasive lung adenocarcinoma and identify the candidates who may benefit from immunotherapy. ADVANCES IN KNOWLEDGE:The nomogram based on dual-layer spectral detector CT can predict the probability of PD-L1 expression in invasive lung adenocarcinoma and may help personalized immunotherapy decisions.

Endoplasmic reticulum-associated degradation (ERAD) is a critical protein quality control mechanism that also regulates lipid metabolism and calcium homeostasis. Dysregulation of ERAD and unfolded protein response underlies diseases including cancer, neurodegenerative disorders, and metabolic syndromes. Small molecule modulators of ERAD could enable mechanistic discovery and therapeutic intervention, but few have been identified. Using a high-content screening, we discovered several ERAD-modulating compounds, including NCATS-SM0225, an ERAD inhibitor that unexpectedly binds all three isoforms of VDAC, outer mitochondrial membrane proteins enriched at mitochondria-associated membranes. This led us to discover an essential role for VDACs in ERAD and ER-phagy. NCATS-SM0225 elevates cytosolic, ER, and mitochondrial calcium through calcium influx and IP3R–MCU activity. This calcium imbalance strengthens VDAC1–IP3R coupling and activates PERK, which phosphorylates STIM1 and drives degradation of key ERAD regulators. Loss of these components amplifies PERK signaling and selectively kills cancer cells while sparing normal cells. These findings uncover a cancer-specific role of VDACs in ERAD regulation and calcium signaling, highlighting a therapeutically actionable vulnerability. Here the authors present NCATS-SM0225, a small molecule that inhibits ERAD and selectively kills cancer cells by binding VDACs, disrupting calcium homeostasis, and triggering the PERK-STIM1 pathway to degrade ERAD regulators.

Liver diseases pose a significant global health burden. This review systematically elucidates the crucial role of exercise as a non-pharmacological intervention in the prevention and treatment of various liver conditions, including metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-related liver disease (ALD), viral hepatitis, liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Exercise effectively delays disease progression and improves patients' quality of life through multi-targeted mechanisms, such as improving glucose and lipid metabolism, enhancing insulin sensitivity, regulating immune-inflammatory responses, inhibiting hepatic stellate cell activation, and remodeling the tumor microenvironment. Future research should focus on developing individualized, precise exercise prescriptions and further exploring its molecular mechanisms by integrating multi-omics technologies, thereby providing innovative strategies for the comprehensive management of liver diseases.

BACKGROUND:Acetaminophen (APAP) is a widely used analgesic and antipyretic agent that is safe at therapeutic doses. However, due to its extensive misuse, APAP-induced liver injury has become a major public health concern. Although mesenchymal stem/stromal cells (MSCs) represent a promising emerging therapy for APAP-induced liver injury, considerable research has focused on enhancing their efficacy, notably through genetic modification. Fibroblast growth factor 21 (FGF21), an endocrine hormone activated by metabolic stress, is known to regulate energy homeostasis, glucose and lipid metabolism, and to promote the homing of MSCs to sites of injury. Consequently, this study was designed to determine whether genetically engineering MSCs to overexpress FGF21 (FGF21-MSCs) augments their therapeutic potential against APAP-induced acute liver injury (ALI). METHODS:In this investigation, MSCs were employed as a platform for FGF21 gene delivery. The MSCs were transduced with lentiviral vectors encoding the FGF21 gene to facilitate sustained FGF21 overexpression. We subsequently assessed the therapeutic potential of these FGF21-MSCs in a murine model of APAP-induced ALI. The extent of liver injury was comprehensively evaluated. Furthermore, the underlying mechanisms were elucidated using techniques including immunohistochemistry, immunofluorescence, and flow cytometry. RESULTS:Our results demonstrated that FGF21-MSCs significantly enhanced the therapeutic efficacy of conventional MSCs against APAP-induced ALI via a biphasic mechanism: attenuating oxidative stress and inflammation during the acute injury phase, while actively fostering tissue repair during the subsequent regenerative phase. This protective effect is primarily mediated through the enhancement of macrophage phagocytic capacity, thereby accelerating tissue repair and regeneration. CONCLUSIONS:Our findings demonstrate that FGF21-MSCs significantly augment therapeutic efficacy against APAP-induced ALI in mice, thereby yielding critical insights and revealing novel therapeutic targets for ALI prevention and treatment.

BACKGROUND & AIMS:Alcohol-associated liver disease (ALD) is a worldwide public health concern with limited therapeutic options. The gut microbiota plays a crucial role in its pathogenesis, yet the therapeutic potential of specific microbial species and metabolites remains largely unexplored. METHODS:We investigated the role of Fusobacterium nucleatum (F. nucleatum) in ALD using human stool samples, a NIAAA mouse model, and multi-omics approaches. Liver injury was evaluated by biochemical, histological, and molecular analyses. Gut microbiota composition was assessed by 16S rDNA sequencing, while metabolomics and proteomics identified functional pathways. Mannose rescue experiments and Fbp1 inhibition were used to validate the proposed mechanism. RESULTS:F. nucleatum abundance was increased in patients with ALD and showed an inverse association with liver injury severity. Supplementation with F. nucleatum in ALD mice significantly attenuated hepatic steatosis, inflammation, and oxidative stress. Mechanistically, F. nucleatum-derived mannose upregulated and stabilized the hepatic gluconeogenic enzyme Fbp1 in ALD mice, suppressing the PI3K/AKT/mTOR pathway and restoring metabolic homeostasis. Inhibition or knockdown of Fbp1 abolished mannose-mediated protection. Furthermore, mannose promoted the proliferation of Akkermansia muciniphila, improved gut barrier integrity, and reduced systemic endotoxemia. Heat-killed F. nucleatum failed to reproduce these effects, indicating that active metabolite secretion was required. CONCLUSION:This study identifies F. nucleatum as a commensal with hepatoprotective effects in ALD, acting through a mannose-Fbp1 signaling axis and gut microbiota modulation. These findings highlight mannose as a microbiota-derived therapeutic candidate and suggest that targeting bacterial metabolites, rather than live bacterial administration, may represent a promising strategy for ALD intervention. IMPACT AND IMPLICATIONS:Alcohol-associated liver disease (ALD) remains a critical clinical issue with few effective treatments. Our study reveals Fusobacterium nucleatum (F. nucleatum) as a novel commensal bacterium that mitigates ALD through modulation of gut metabolites and microbial reorganization. Specifically, we demonstrate that mannose, a key metabolite derived from F. nucleatum, activates the metabolic regulator Fbp1 and suppresses the PI3K/AKT/mTOR pathway, thereby conferring hepatoprotection. Furthermore, supplementation with F. nucleatum enriches Akkermansia muciniphila, strengthening intestinal barrier function and promoting gut-liver axis homeostasis. These findings position mannose as a promising microbiota-derived therapeutic agent for ALD, effectively linking microbial intervention with host metabolic reprogramming.

Macrophages play a critical role in sepsis, a life-threatening systemic inflammatory syndrome that necessitates urgent therapeutic intervention. Unfortunately, no approved drugs currently target this specific pathological mechanism. In this study, we identify Igalan, a natural compound that selectively disrupts macrophage-mediated inflammatory cascades in macrophages. Mechanistic studies demonstrate that Igalan alleviates oxidative stress and maintains mitochondrial integrity. Crucially, we reveal that Igalan covalently modifies the NLRP3 (NLR family pyrin domain containing 3) NACHT domain, thereby irreversibly suppressing inflammasome activation and subsequent pro-inflammatory signaling. In vivo studies demonstrate potent therapeutic effects of Igalan, mitigating systemic inflammation in LPS-challenged zebrafish and providing protection against pulmonary injury and intestinal barrier dysfunction in murine sepsis models. Collectively, our work establishes Igalan as a covalent NLRP3 inhibitor with translational potential for sepsis treatment.

BACKGROUND:Hypertriglyceridaemia-induced acute pancreatitis (HTG-AP) is frequently complicated by acute lung injury (ALI), which worsens prognosis. Oleic acid (OA), a major circulating free fatty acid, may play a key role, but the underlying mechanism remains unclear. OBJECTIVE:To investigate the relationship between plasma OA and HTG-AP-associated ALI and to explore the mechanism by which OA disrupts endothelial barrier through PIEZO1-mediated impairment of fatty acid oxidation (FAO). DESIGN:This study used clinical sample analysis, an HTG-AP mouse model and OA-stimulated human umbilical vein endothelial cells. The association between OA and ALI was evaluated, and PIEZO1 was identified as a potential OA target through calcium imaging, transcriptomics and the Human Protein Atlas. Genetic/pharmacological interventions, lipidomics, Seahorse assays and barrier function tests were used to characterise FAO impairment and barrier disruption. NR4A1 regulation of CPT1A was investigated through transcriptomic and ChIP assays. Finally, the pathway's function was validated in mice with endothelial-specific Piezo1 knockdown. RESULTS:Clinical and animal data showed elevated plasma OA in HTG-AP, positively associated with ALI incidence and severity. Multidimensional data identified PIEZO1 as a key target mediating OA-induced endothelial dysfunction. Mechanistically, OA activated and upregulated PIEZO1, which suppressed NR4A1 expression, leading to downregulation of CPT1A and impaired FAO, ultimately disrupting the endothelial barrier. Endothelial-specific Piezo1 knockdown significantly alleviated HTG-AP-associated ALI in mice. CONCLUSION:OA promotes endothelial barrier dysfunction and exacerbates HTG-AP-associated ALI via the Piezo1/NR4A1/CPT1A axis by impairing FAO, offering a novel mechanistic insight and identifying potential therapeutic targets for HTG-AP-associated ALI.

Human peripheral blood exhibits molecular and cellular heterogeneity across populations, yet the underlying mechanisms remain unclear. We present the Chinese Immune Multi-Omics Atlas (CIMA), characterizing molecular variations linked to sex, age, and genetic variants through multi-omics analysis of more than 10 million circulating immune cells from 428 Chinese adults. CIMA established an enhancer-driven gene regulatory network comprising 237 robust regulons; identified 9600 eGenes and 52,361 caPeaks at cell type resolution; and revealed pleiotropic associations among immune-related disease risk loci, cis-expression quantitative trait loci (QTLs), and chromatin accessibility QTLs. Furthermore, the cell language model CIMA-CLM predicted chromatin accessibility and evaluated the effects of noncoding variants from chromatin sequences and gene expression. CIMA provides a comprehensive reference for immune-related disease research.

Objective To evaluate the protective effect of miR-486-5p modified umbilical cord mesenchymal stem cells(UCMSCmiR-486)against radiation-induced heart damage(RIHD)and explore the mechanism.Methods 20 Gy of 60Co g-ray was used to establish a model for radiation-induced cardiomyocytes and cardiac damage to mice before UCMSCmiR-486(1×106 cells per mouse)was treated after radiation.Cell proliferation was detected using CCK-8 kit 48 hours post-treatment.Apoptosis,changes of mitochondrial membrane potential,and the opening of the mitochondrial permeability transition pore of cardiomyocytes were detected by flow cytometry.Small animal ultrasound was used to detect and analyze the cardiac function of mice 42 days later.Changes of cardiac histopathology were detected via HE staining and Masson staining.The ultrastructure of myocardia was observed under a transmission electron microscope(TEM).Real-time quantitative PCR(RT-qPCR)and Western blotting were performed to detect the expressions of ferroptosis-related genes and proteins.Results UCMSCmiR-486 markedly reduced radiation-induced apoptosis and especially reactive oxygen species(ROS)levels in AC16 cardiomyocytes and restored both mitochondrial membrane potential and membrane permeability.Intravenous administration of UCMSCmiR-486 via the tail vein significantly increased ejection fraction and shortening fraction in irradiated mouse hearts,decreased the area of myocardial fibrosis,and mitigated mitochondrial ultrastructural damage UCMSCmiR-486 could inhibit ferroptosis of radiated cardiomyocytes and cardiac tissues of mice by modulating the expressions of ferroptosis-related markers,especially acyl-CoA synthetase long chain family member 4(ACSL4)and glutathione peroxidase 4(GPX4).Conclusion UCMSCmiR-486 can mitigate RIHD by inhibiting ferroptosis.This finding is expected to offer a new strategy for the clinical translation of mesenchymal stem cells.