Triphenyltin chloride (TPTC), a member of the organotin family, has been widely restricted due to its endocrine-disrupting effects. Nevertheless, TPTC continues to be detected in aquatic environments and poses potential health risks owing to its persistence and bioaccumulation. Although previous studies have shown that triphenyltin compounds can disrupt lipid homeostasis through nuclear receptor pathways involving retinoid X receptor (RXR) and peroxisome proliferator-activated receptors (PPARs), whether TPTC exerts hepatocytotoxicity through direct metabolic targets remains unclear. This study employed a metabolomics-driven target discovery strategy to analyze intracellular metabolite extracts from HepG2 cells exposed to TPTC for 24 h, aiming to investigate the underlying molecular mechanisms of TPTC-induced metabolic toxicity. Untargeted global metabolomics analysis revealed that TPTC exposure caused significant disturbances in hepatic lipid metabolism, characterized by the accumulation of medium- and long-chain fatty acids and depletion of key metabolites associated with fatty acid β-oxidation. Pathway enrichment analysis and protein–protein interaction network analysis further indicated that two mitochondrial dehydrogenases involved in fatty acid catabolism─hydroxysteroid 17β-dehydrogenase 10 (HSD17B10) and hydroxyacyl-CoA dehydrogenase (HADH)─are potential metabolic targets responsible for the observed alterations. Molecular docking, surface plasmon resonance, and cellular thermal shift assays confirmed direct interactions between TPTC and both HSD17B10 and HADH, with binding affinities at the micromolar level. Functional validation demonstrated that TPTC disrupts mitochondrial respiratory function and redox balance by interfering with HADH- and HSD17B10-dependent generation of acetyl-CoA and NADH, leading to mitochondrial dysfunction and oxidative stress. In summary, this study reveals a previously underappreciated mechanism of TPTC toxicity involving mitochondrial metabolism, extending the current understanding of its toxicological pathways beyond nuclear receptor-mediated signaling to include direct disruption of mitochondrial energy and redox metabolism.
Formononetin, an isoflavone compound, has been extensively researched due to its various biological activities, including a potent protective effect on the cardiovascular system. However, the impact of formononetin on cardiac fibrosis has not been investigated. In this study, C57BL/6 mice were used to establish cardiac fibrosis animal models by subcutaneous injecting of isoproterenol (ISO) and formononetin was orally administrated. The results showed that formononetin reversed ISO-induced heart stiffness revealed by early-to-atrial wave ratio (E/A ratio). Masson staining, western blot, immunohistochemistry and real-time PCR exhibited that the cardiac fibrosis and fibrosis-related proteins (collage III, fibronectin, TGF-β1, α-SMA, and vimentin) and genes ( Col1a1 , Col3a1 , Acta2 and Tgfb1 ) induced by ISO were significantly suppressed by formononetin. Furthermore, by combining metabolomics and network pharmacology, we found three important targets ( ALDH2 , HADH , and MAOB ), which are associated with mitochondrial function, were involved in the beneficial effect of formononetin. Further validation revealed that these three genes were more abundance in cardiomyocyte than in cardiac fibroblast. The mRNA expression of ALDH2 and HADH were decreased, while MOAB was increased in cardiomyocyte upon ISO treatment and these phenomena were reversed by formononetin. In addition, we investigated mitochondrial membrane potential and ROS production in cardiomyocytes, the results showed that formononetin effectively improved mitochondrial dysfunction induced by ISO. In summary, we demonstrated that formononetin via regulating the expressions of ALDH2 , HADH, and MAOB in cardiomyocyte to improve mitochondrial dysfunction and alleviate β-adrenergic activation cardiac fibrosis.
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