A mushroom-derived bioactive compound, Vialinin A, attenuates doxorubicin-induced cardiotoxicity via SUCLG2-associated mitochondrial protection

Doxorubicin (DOX)-induced cardiotoxicity remains a major limitation of cancer therapy and is closely linked to oxidative stress and mitochondrial injury. However, effective natural-product-based strategies for mitigating this complication are still lacking. Here, we investigated the cardioprotective effects of Vialinin A (Via), a bioactive compound isolated from the edible mushroom Thelephora vialis, using cardiomyocytes, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), and a chronic mouse model of DOX-induced cardiotoxicity. Via attenuated DOX-induced cardiac injury, improved cardiac function, reduced reactive oxygen species accumulation, restored mitochondrial membrane potential, and improved ATP production. DARTS-based proteomic screening identified succinyl-CoA ligase GDP-forming subunit beta (SUCLG2) as a candidate Via-interacting protein. DARTS validation, CETSA, molecular docking, and molecular dynamics analyses provided convergent evidence consistent with cellular engagement of SUCLG2 by Via. Via increased the protease resistance and thermal stability of SUCLG2 and partially reversed the DOX-associated reduction in SUCLG2 expression. Functionally, SUCLG2 knockdown weakened Via-mediated mitochondrial protection and reduced the associated recovery of PI3K-AKT phosphorylation, whereas SUCLG2 overexpression partially alleviated DOX-induced mitochondrial dysfunction. Via also partially corrected DOX-associated changes in tricarboxylic acid cycle-related metabolites, consistent with improved mitochondrial metabolic homeostasis. Together, these findings identify Via as a mushroom-derived bioactive compound with cardioprotective activity against DOX-induced injury and support SUCLG2 as a Via-engaged, functionally relevant protein associated with mitochondrial protection.