Regulating Sirtuin 3-mediated mitochondrial dynamics through vanillic acid improves muscle atrophy in cancer-induced cachexia

Cancer cachexia is a cancer-associated disease characterized by gradual body weight loss due to pathologic muscle and fat loss, but effective treatments are still lacking. Here, we investigate the possible effect of vanillic acid (VA), known for its antioxidant, anti-inflammatory, and anti-obesity effects, on mitochondria-mediated improvement of cancer cachexia. We utilized cachexia-like models using CT26 colon cancer and dexamethasone. VA improved representative parameters of cancer cachexia including body weight loss and increased serum intereukin-6 levels. VA also attenuated muscle loss in the tibialis anterior and gastrocnemius muscles, inhibited proteolytic markers including muscle RING-finger protein-1 (MURF1) and muscle atrophy F-box (MAFbx) and improved mitochondrial function through alteration of sirtuins 3 (SIRT3) and mitofusin 1 (MFN1). Importantly, silencing the SIRT3 gene abolished the effect of VA, indicating that SIRT3 is important in the mechanism of action of VA. Overall, we suggest using VA as a novel therapeutic agent that can fundamentally treat and recover muscle atrophy in cancer cachexia patients. Mechanistic insights into vanillic acid reveal its role in restoring muscle mass, reducing cytokines, and enhancing mitochondrial function via SIRT3 modulation, underscoring its therapeutic potential in muscle atrophy induced by cancer cachexia.