Signal Transduction and Targeted Therapy
·
2024
·Vol. 9
·期 1
·1-17
·
IF 40.8
Peng Fu,Liao Minru,Jin Wenke,Liu Wei,Li Zixiang,Fan Zhichao,Zou Ling,Chen Siwei,Zhu Lingjuan,Zhao Qian,Zhan Gu,Ouyang Liang,Peng Cheng,Han Bo,Zhang Jin,Fu Leilei
Sirtuin 3 (SIRT3) is well known as a conserved nicotinamide adenine dinucleotide + (NAD + )-dependent deacetylase located in the mitochondria that may regulate oxidative stress, catabolism and ATP production. Accumulating evidence has recently revealed that SIRT3 plays its critical roles in cardiac fibrosis, myocardial fibrosis and even heart failure (HF), through its deacetylation modifications. Accordingly, discovery of SIRT3 activators and elucidating their underlying mechanisms of HF should be urgently needed. Herein, we identified a new small-molecule activator of SIRT3 (named 2-APQC) by the structure-based drug designing strategy. 2-APQC was shown to alleviate isoproterenol (ISO)-induced cardiac hypertrophy and myocardial fibrosis in vitro and in vivo rat models. Importantly, in SIRT3 knockout mice, 2-APQC could not relieve HF, suggesting that 2-APQC is dependent on SIRT3 for its protective role. Mechanically, 2-APQC was found to inhibit the mammalian target of rapamycin (mTOR)-p70 ribosomal protein S6 kinase (p70S6K), c-jun N-terminal kinase (JNK) and transforming growth factor-β (TGF-β)/ small mother against decapentaplegic 3 (Smad3) pathways to improve ISO-induced cardiac hypertrophy and myocardial fibrosis. Based upon RNA-seq analyses, we demonstrated that SIRT3-pyrroline-5-carboxylate reductase 1 (PYCR1) axis was closely assoiated with HF. By activating PYCR1, 2-APQC was shown to enhance mitochondrial proline metabolism, inhibited reactive oxygen species (ROS)-p38 mitogen activated protein kinase (p38MAPK) pathway and thereby protecting against ISO-induced mitochondrialoxidative damage. Moreover, activation of SIRT3 by 2-APQC could facilitate AMP-activated protein kinase (AMPK)-Parkin axis to inhibit ISO-induced necrosis. Together, our results demonstrate that 2-APQC is a targeted SIRT3 activator that alleviates myocardial hypertrophy and fibrosis by regulating mitochondrial homeostasis, which may provide a new clue on exploiting a promising drug candidate for the future HF therapeutics.
研究领域:
心血管药理学
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分子生物学
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细胞生理学
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高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Shan Yang,Cheng Chen,Yang Xiong,Jiaxiu Ling,Lijuan Chen,Chunxia Wang,Xiaoyu Zhang,Jixiu Yi,Wenzhen Deng,Xiaohui Liao
Objective Pirfenidone (PFD) has been used to treat kidney fibrosis. However, the effects of PFD on obesity-related kidney injury and the underlying mechanisms are still poorly understood. Methods Male C57BL/6 J mice were fed a high-fat diet (HFD) for 20 weeks to induce kidney injury, and PFD was added to the feed of the mice in the PFD group beginning at 8 weeks. The controls were fed a normal control diet (NCD), and half of the mice were similarly treated with PFD. Indicators associated with lipid metabolism and kidney injury were assessed in vivo. Furthermore, human proximal tubular epithelial (HK−2) cells and human primary renal proximal tubule epithelial cells (PTECs) were incubated with palmitate (PA) and PFD, to investigate the effect of PFD on tubule cell injury in vitro. Single-cell sequencing analysis, molecular docking, and coimmunoprecipitation were subsequently used to explore the mechanisms of PFD action. Results PFD ameliorated metabolic abnormalities, inflammatory responses and oxidative stress induced by an HFD. PFD alleviated renal fatty acid oxidation and injury indicators in the HFD-fed mice and PA-treated renal tubular cells. PFD reversed the HFD/PA-induced decrease in SIRT3 protein expression. Moreover, transfection with si-SIRT3 abolished the beneficial effects of PFD on kidney injury and lipid metabolism in HK-2 cells. Conclusion In summary, our data revealed that PFD could mitigate obesity-related kidney injury in a SIRT3-dependent manner.
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高影响因子
Bone & Joint Research
·
2026
·Vol. 15
·期 9
·1123
·
IF 5.5
Yiqiong Nie,Jiefu Zhou,Xueying Zhang,Yang Chen,Tao Zhang,Wei Peng,Linfeng Wang,Shouan Zhu,Hongbin Lu
Aims Mitochondrial redox homeostasis is closely linked to the ageing processes of tendons, whether in normal or pathological conditions. This study employed an innovative approach to examine the role of sirtuin 3 (SIRT3) in mitochondrial dysfunction in the aged murine supraspinatus tendon (ST). Methods Pathological changes and collagen organization in tendons, along with variations in SIRT3 levels and oxidative stress, were initially assessed in mice of different ages. In vitro experiments were then performed to evaluate the effects of oxidative senescence on tendon cells, including cellular activity, phenotype, and collagen secretion. Finally, we explored the underlying mechanisms via which SIRT3 regulates mitochondrial redox homeostasis. Results Histological and immunofluorescence analyses revealed a decline in SIRT3 levels within tenocytes as ageing progressed, accompanied by mitochondrial dysfunction and ageing-related phenotypes. The reduction in SIRT3 with age led to an increase in reactive oxygen species levels in tendon cells. However, enhancing SIRT3 expression in cells under oxidative stress was found to activate the SOD2 and Keap1/Nrf2/HO-1 signalling pathways, effectively reversing cellular senescence. Conclusion SIRT3 plays a pivotal role in maintaining mitochondrial redox homeostasis in ST by regulating the mitochondrial antioxidant network to mitigate ageing and oxidative stress in tendon cells. Targeting SIRT3 in ST degeneration may offer a promising therapeutic approach. Cite this article: Bone Joint Res 2026;15(9):1123–1135.
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EUROPEAN JOURNAL OF PHARMACOLOGY
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2022
·
IF 5.195
Guanghui Ren,Yan Ma,Xingjie Wang,Zhaodi Zheng,Guorong Li
Non-small cell lung cancer (NSCLC) has the highest incidence and mortality in the world. Aspirin has been reported to promote apoptosis , inhibit proliferation, stemness, angiogenesis , cancer-associated inflammation and migration in NSCLC. But the effect of aspirin on aerobic glycolysis in NSCLC is less reported. In the present study, we investigated whether aspirin blocked aerobic glycolysis of NSCLC cells to inhibit proliferation. Our results showed that aspirin inhibited viability, PCNA expression, ability of colony formation, dimished extracellular acidification rate (ECAR), oxygen consumption rate (OCR) and production of pyruvic acid and lactic acid, accompanied with reduced mitochondrial membrane potential (MMP), PGC-1α expression and ROS production, indicating mitochondrial dysfunction in NSCLC cells. AMPK and mitochondrial-localized deacetylase sirtuin 3 (SIRT3) were identified as the relevant molecular targets in glycolysis, but mechanism and relationship between AMPK and SIRT3 for aspirin induced glycolysis inhibition remain unknown in cancer cells. The investigation of underlying mechanism indicated that aspirin activated AMPK pathway to inhibit aerobic glycolysis and proliferation by upregulating SIRT3 after application of compound C (CC), an inhibitor of AMPK activity or SIRT3 siRNA . Upon activation of SIRT3, aspirin promoted the release of hexokinase-II (HK-II) from mitochondrial outer membrane to cytosol by deacetylating cyclophilin D (CypD). Consistently, aspirin significantly inhibited the growth of NSCLC xenografts and exhibited antitumor activity probably through AMPK/SIRT3/HK-II pathway in vivo . Collectively, AMPK/SIRT3/HK-II pathway plays a critical role in anticancer effects of aspirin, and our findings might serve as potential target for clinical practice and chemoprevention of aspirin in NSCLC.
研究领域:
肿瘤学
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药理学
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细胞生物学
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分子生物学
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PubMed
高影响因子
CELLULAR AND MOLECULAR LIFE SCIENCES
·
2026
·
IF 6.5
Huang Yafei,Liu Hong,Tong Chao,Wang Zhimin,Xu Miaomiao,Dong Mengqi,Rao Rongjia,Wang Xianqiang,Feng Wei,Hu Zhan,Xu Fei,Zhao Wei,Wang Li,Hu Shengshou,Zhou Bingying
Drug-induced mitochondrial toxicity is a major contributing factor to cardiotoxicity, which can cause drug attrition and adverse cardiac events. To assess the toxicity of anti-inflammatory agents, we used adult human primary cardiomyocytes (hPCMs) to screen 18 clinically available anti-inflammatory drugs in a high-content manner, and revealed widespread mitochondrial dysfunction without affecting cell viability. Nabumetone, a representative nonsteroidal anti-inflammatory drug with profound mitochondrial toxicity, induced mitochondrial fission, inhibited mitophagy, and impaired both electrophysiological and metabolic functions in adult hPCMs. Mechanistically, we uncovered that nabumetone (Nab) exerted its toxic effects through the prostaglandin E2- E-type prostanoid receptor 4 (PGE 2 -EP 4 ) pathway, which was essential for its anti-inflammatory functions. To find an alternative route to ameliorate mitochondrial damage, we identified SIRT3 as a downstream target of nabumetone. Its mRNA, protein, and activity levels were significantly reduced upon nabumetone treatment. SIRT3 activator honokiol exhibited protective potential against NSAID-induced mitochondrial toxicity both in hPCMs and in nabumetone-treated mice. Finally, through screening mitochondrial liability in various common cardiomyocyte models, we identified mitochondrial abundance as an important determinant of the sensitivity of cells towards mitochondrial toxicants. Our study demonstrates the vast presence of mitochondrial dysfunction in human adult cardiomyocytes imposed by clinically used anti-inflammatory drugs, and identified both toxicity and protective pathways that may serve future therapeutic purposes.
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Annals of Translational Medicine
·
2022
·
IF 3.616
Lei Wang,Yanling Ding,Yanhui Bai,Jian Shi,Jia Li,Xiuli Wang
Background The lung is one of the most sensitive organs, and is vulnerable to injury caused by limb ischemia-reperfusion (LIR). Dexmedetomidine, an anesthetic adjunct, has been shown to have therapeutic effects on lung injury secondary to LIR. This study aimed to investigate the role of dexmedetomidine in ameliorating LIR-induced lung injury in a mouse model of bilateral hind LIR. Methods In this study, 75 mice were randomly divided into 5 groups to prepare the LIR model. After the model was established, arterial blood was extracted for blood gas analysis. The pathological changes of lung tissue, lung wet/dry weight ratio, arterial blood gas analysis, detection of myeloperoxidase (MPO) activity, the content of reactive oxygen species (ROS), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) in oxidative stress indexes, mitochondrial membrane potential (MMP), adenosine triphosphate (ATP) content and cytochrome c content were measured, and the relative protein expression levels of sirtuin-3 (SIRT3) and apoptosis factor Bcl-2 related X protein (Bax), B-cell Lymphoma 2 (Bcl-2), cleaved caspase 3, and nuclear factor erythroid 2-related factor 2 (Nrf2) and cytoplasmic heme oxygenase-1 (HO-1). Results Pretreatment with dexmedetomidine dramatically ameliorated LIR-induced lung injury, the wet/dry weight ratio, the arterial blood gas parameters, and enhanced SIRT3 expression. Moreover, dexmedetomidine significantly inhibits ROS and MDA level and restores antioxidant enzyme activities (SOD, GSH-Px). Of note, dexmedetomidine suppressed LIR-induced lung tissue apoptosis by modulating apoptosis-associated protein such as Bax, Bcl-2, and cleaved caspase 3. Moreover, dexmedetomidine inhibited the LIR-induced decreases in MMP, ATP levels, and the release of cytochrome c of LIR to maintain mitochondrial function. Latest study has shown that activating Nrf2 could promote SIRT3 expression to alleviate IR injury. Intriguingly, dexmedetomidine could facilitate nuclear Nrf2 and cytoplasmic HO-1 expression. Conclusions Our findings suggest that dexmedetomidine protects against LIR-induced lung injury by inhibiting the oxidative response, mitochondrial dysfunction and apoptosis. The mechanism appears to be at least partly mediated through the upregulation of SIRT3 expression.
研究领域:
药理学
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病理生理学
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呼吸医学
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分子生物学
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DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2025
·
IF 8.3
Mengdi Cui,Yi An,Jingling Zhao,Miaoxin Hui,Zhili Xiong,Bing Guan,Yinfeng Shen,Yinshui Zou,Chengyin Li,Rui Wang
Background: Acute kidney injury (AKI) is a leading complication of sepsis, necessitating the exploration of novel treatment modalities. The traditional Chinese medicine Dahuang Gancao Decoction (DHGC) has potential in the treatment of sepsis-associated acute kidney injury (SA-AKI). However, its specific mechanisms require further investigation. Purpose: This study aimed to validate the antiferroptotic effects of DHGC in the treatment of SA-AKI in vivo and in vitro . Methods: C57BL/6 mice and C57BL/6-background sirtuin-3 (SIRT3) -/- mice were induced with Reagents Lipopolysaccharide (LPS), while normal and si-SIRT3 human proximal tubular epithelial (HK-2) cells were induced with erastin to establish a ferroptosis phenotype, followed by DHGC treatment. First, the DHGC components were identified via liquid chromatography-tandem mass spectrometry (LC‒MS/MS), and the potential active components were further screened through comparison with the high-performance liquid chromatography (HPLC) reference standards. Ferroptosis levels and the protective mechanisms of DHGC in vivo and in vitro were evaluated using biochemical assays, transmission electron microscopy, immunohistochemistry, immunofluorescence, and Cell Counting Kit-8 (CCK-8) assays. Key pathways were identified by RNA-seq and validated via enzyme-linked immunosorbent assay (ELISA) and western blotting. Finally, the potential active components were subjected to molecular docking with SIRT3 to select candidate monomers for subsequent in vitro functional validation. Results: LPS was used to induce SA-AKI in mice, and erastin was used to induce ferroptosis in HK-2 cells. DHGC can improve renal function, increase cell viability, and reverse abnormal changes in key ferroptosis indicators. Mechanistically, the expression levels of SIRT3/nuclear factor erythroid-2 related factor 2 (NRF2) pathway-associated proteins were downregulated, and NRF2 nuclear translocation was restricted after modeling; in contrast, DHGC upregulated the expression of SIRT3/NRF2 pathway-related proteins, promoted NRF2 nuclear translocation, and activated downstream glutathione peroxidase 4 (GPX4) expression. Importantly, DHGC failed to improve the above indicators in SIRT3-deficient models. Potential active components of DHGC were screened via HPLC reference standard comparison, and subsequent molecular docking with SIRT3 identified candidate monomers. These monomers exerted ferroptosis-inhibiting effects consistent with those of the parent compound DHGC. Conclusions: The present study offers the first demonstration that DHGC retards SA-AKI progression through stimulating SIRT3-driven deacetylation of NRF2, promoting NRF2 nuclear translocation, and inhibiting ferroptosis. These findings suggest that DHGC is a potential therapeutic candidate for SA-AKI, warranting further clinical investigation.
研究领域:
中医中药
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肾脏病学
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分子生物学
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药理学
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氧化应激
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Advanced Science
·
2025
·
IF 14.1
Xinfeng Zhou,Xin Tian,Jianan Chen,Yantong Li,Nanning Lv,Hao Liu,Tao Liu,Huilin Yang,Xi Chen,Yong Xu,Fan He
Extracellular matrix (ECM) derived from mesenchymal stem cells regulates antioxidant properties and bone metabolism by providing a favorable extracellular microenvironment. However, its functional role and molecular mechanism in mitochondrial function regulation and aged bone regeneration remain insufficiently elucidated. This proteomic analysis has revealed a greater abundance of proteins supporting mitochondrial function in the young ECM (Y-ECM) secreted by young bone marrow-derived mesenchymal stem cells (BMMSCs) compared to the aged ECM (A-ECM). Further studies demonstrate that Y-ECM significantly rejuvenates mitochondrial energy metabolism in adult BMMSCs (A-BMMSCs) through the promotion of mitochondrial respiratory functions and amelioration of oxidative stress. A-BMMSCs cultured on Y-ECM exhibited enhanced multi-lineage differentiation potentials in vitro and ectopic bone formation in vivo. Mechanistically, silencing of silent information regulator type 3 (SIRT3) gene abolished the protective impact of Y-ECM on A-BMMSCs. Notably, a novel composite biomaterial combining hyaluronic acid methacrylate hydrogel microspheres with Y-ECM is developed, which yielded substantial improvements in the healing of bone defects in an aged rat model. Collectively, these findings underscore the pivotal role of Y-ECM in maintaining mitochondrial redox homeostasis and present a promising therapeutic strategy for the repair of aged bone defects.
研究领域:
再生医学
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细胞生物学
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生物材料学
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PubMed
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BIOCHEMICAL PHARMACOLOGY
·
2026
·
IF 5.6
Mingxing Sui,Shuying Wu,Qingqing Song,Siyao Chen,Yingli Lu
Polycystic ovary syndrome (PCOS) is characterized by a constellation of symptoms, including menstrual cycle irregularities, hyperandrogenism, and polycystic ovarian morphology. Despite extensive research efforts, a thorough understanding of the underlying pathophysiology and effective treatment options for PCOS remain elusive. In this study, ovarian tissues from dehydroepiandrosterone (DHEA)-induced PCOS mice and control mice underwent mRNA sequencing. Through a comprehensive bioinformatics analysis, we systematically examined the sequencing data, and one cut homeobox 2 (Onecut2), a significantly downregulated gene in PCOS mice, was identified and selected as the primary research target. Our findings determined that the overexpression of Onecut2 efficiently alleviated pathological changes and reduced mitochondrial dysfunction in DHEA-induced PCOS mice. Additionally, Onecut2 was found to be expressed at a low level in human ovarian granulosa KGN cells treated with dihydrotestosterone (DHT). Gain-of-function and loss-of-function experiments uncovered that Onecut2 played a role in inhibiting apoptosis and mitochondrial damage in DHT-treated KGN cells. Dual-luciferase reporter assays demonstrated that Onecut2 overexpression activated the transcriptional activity of the sirtuin 3 (SIRT3) promoter, thereby controlling the function of granulosa cells. Mechanistic investigation revealed that the mRNA stability of Onecut2 was regulated by methyltransferase-like 3 (METTL3) via m6A modification. Collectively, this study demonstrates that Onecut2 exerts an inhibitory role in PCOS progression by transcriptionally regulating SIRT3 expression and that this regulation is influenced by METTL3-mediated m6A methylation.
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Food Frontiers
·
2026
·Vol. 7
·期 6
·e70370
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IF 6.3
Jingzheng Li,Honglin Jiang,Jianwen He,Wen Yao
Lactation represents one of the most metabolically demanding physiological states in mammals, characterized by heightened bioenergetic flux that increases electron transport chain (ETC) activity. This metabolic feature renders the maternal liver highly susceptible to mitochondrial redox imbalance under heat stress (HS). Baicalin (BAI), a nature food-derived flavonoid from Scutellaria baicalensis , is known for its antioxidant and hepatoprotective properties, but its mechanism in lactational HS has not been fully elucidated. Here, we demonstrate that BAI exerts its hepatoprotective effects by targeting the Sirt3–NDUFS1 axis to preserve mitochondrial complex I redox homeostasis in lactating mammals. Using a lactational HS mouse model and AML-12 hepatocytes, we demonstrate that BAI attenuates HS-induced hepatic injury, oxidative stress, and mitochondrial dysfunction. Mechanistically, BAI restored the expression of the mitochondrial deacetylase Sirt3, which was suppressed by HS. This led to deacetylation of the complex I core subunit NDUFS1, thereby rescuing complex I activity and limiting mitochondrial reactive oxygen species (mtROS) overproduction. BAI also attenuated secondary excessive Pink/PARKIN-dependent mitophagy triggered by mitochondrial respiratory failure, revealing coordinated recovery of electron transport function and downstream mitochondrial quality control. Pharmacological inhibition of Sirt3 abolished the protective effects of BAI on mitochondrial respiration and redox balance, confirming Sirt3 dependence. These findings reveal a BAI–Sirt3–NDUFS1 axis maintaining mitochondrial complex I redox homeostasis, thereby enhancing maternal hepatic resilience to HS. Distinct from previous Sirt3 research in nonreproductive disease models, this work establishes a natural nutritional target strategy specialized for HS lactating subjects, with great potential for maternal nutritional intervention and functional food development.
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高影响因子
INFLAMMATION RESEARCH
·
2026
·Vol. 75
·期 1
·37
·
IF 6.2
Wang Rui,Zou Ziwei,An Yi,Wang Liulin,Li Chengyin,Zou Yinshui,Wang Guangzhi
Background Acute kidney injury (AKI), characterized by rapid renal dysfunction and high mortality, is critically driven by ferroptosis, an iron-dependent form of cell death. While PTEN-induced kinase 1 (PINK1) and sirtuin 3 (SIRT3) are implicated in mitochondrial homeostasis and ferroptosis regulation, their mechanistic interplay in AKI remains unclear. This study investigated the role of emodin, a natural anthraquinone, in alleviating AKI via SIRT3-mediated PINK1 deacetylation and ferroptosis suppression, focusing on mitochondrial integrity, transferrin (TF) interaction, and redox balance. Materials and methods Male C57BL/6 mice ( n = 6/group), PINK1⁻/⁻, and SIRT3⁻/⁻ mice were pretreated with emodin (40–160 mg/kg, 3 days) before LPS-induced AKI (15 mg/kg). Human renal tubular HK-2 cells were treated with emodin (10–40 µg/ml) and Erastin (0.4 µM, 24 h). Assays included RNA sequencing, immunoprecipitation-mass spectrometry (IP-MS), histopathology (H&E/PAS/PB-DAB staining), ROS/Fe²⁺/GSH quantification, and immunoblotting. Statistical analysis used ANOVA and Student’s t-test. Results Emodin reduced serum creatinine and urea in AKI mice, alongside decreased tubular injury and apoptosis. RNA-seq identified ferroptosis as the central pathway, with emodin upregulating PINK1 expression. IP-MS revealed emodin disrupted PINK1-TF binding via SIRT3-mediated deacetylation, reducing Fe²⁺ accumulation and restoring GPX4 levels. In SIRT3⁻/⁻ and PINK1⁻/⁻ models, emodin’s protective effects were abolished, confirming pathway dependency. Conclusion Emodin mitigates AKI by activating the SIRT3/PINK1 axis, suppressing ferroptosis through cytoplasmic PINK1 deacetylation and TF interaction disruption. These findings highlight SIRT3/PINK1 as a therapeutic target and emodin as a potential agent for AKI management.
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Biology Direct
·
2026
·Vol. 21
·期 1
·113
·
IF 5.5
Wang Wei,Hu Yuanyuan,Xu Yan,Ding Ning,Wei Jiping,Li Cairong,Chen Yong
Background Doxorubicin (DOX) is a widely used broad-spectrum chemotherapy drug, but its severe organ toxic and side effects limit its clinical application. Tetrahydropalmatine (THP) protects against DOX-induced renal injury, yet its underlying mechanism remains unclear. This study aimed to verify THP’s protective effect and explore if it acts via the SIRT3-mediated Nrf2/HO-1 signaling pathway. Methods This study adopted an integrated in vivo and in vitro research system to explore the relevant mechanisms. In vivo, a DOX-induced mouse renal injury model was established with THP intervention; renal function was evaluated by detecting serum creatinine (Scr) and blood urea nitrogen (BUN), while renal injury severity was assessed via urine microalbumin (mALB) and urine albumin/creatinine ratio (UACR). Renal histopathological changes including glomerular injury and tubulointerstitial fibrosis were observed, and subcellular structures such as podocyte integrity and mitochondrial morphology were analyzed by transmission electron microscopy (TEM); additionally, the expression of pathway-related proteins was detected. In vitro, a DOX-induced cell injury model was constructed using mouse podocytes (MPC-5), and Western blot and immunofluorescence techniques were employed to determine the expression of key molecules in the Sirt3-Nrf2/HO-1 pathway, combined with in vivo and in vitro experiments to clarify the underlying mechanism. Results THP significantly attenuated DOX-induced renal injury, improved renal function (reduced Scr/BUN), mitigated histopathological/mitochondrial abnormalities, and preserved podocyte integrity. Molecularly, THP upregulates podocyte markers Nephrin/Podocin, enhances antioxidant capacity (increased GSH, SOD, and CAT, decreased MDA), inhibits inflammation (downregulated IL-6, IL-1β, and TNF-α), and suppresses apoptosis (downregulated Bax/caspase-3, upregulated Bcl-2). Notably, both in vivo and in vitro data link THP’s protection to SIRT3-mediated Nrf2/HO-1 pathway activation. Conclusion THP protects against DOX-induced renal injury in mice. Mechanistically, this may involve activating the SIRT3-mediated Nrf2/HO-1 pathway, improving podocyte function, and inhibiting oxidative stress, inflammation, and apoptosis.
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