Squalene alleviates cancer cachexia-induced muscle atrophy and adipose tissue wasting in CT26 tumor-bearing mice.

Cancer cachexia is a multifactorial metabolic syndrome characterized by progressive loss of body weight, skeletal muscle mass, and adipose tissue, primarily driven by chronic inflammation and systemic metabolic imbalance. Squalene (SQ), a naturally occurring triterpenoid abundant in shark liver oil, exhibits potent antioxidant and anti-inflammatory properties. In this study, we investigated the protective effects of SQ against cancer-induced skeletal muscle and adipose tissue wasting in CT26 tumor-bearing mice. Seven days after CT26 implantation, BALB/c mice were orally administered SQ (150 or 300 mg/kg/d) or saline for 17 days. SQ supplementation significantly attenuated tumor-induced body weight loss and anorexia, along with a reduction in tumor weight in cachectic mice. Furthermore, SQ prevented the loss of muscle mass and fiber cross-sectional area, accompanied by improved grip strength. In the gastrocnemius muscle, SQ inhibited nuclear factor kappa B activation, thereby suppressing the expression of inflammatory cytokines while enhancing antioxidant enzyme expression. These effects collectively reduced protein degradation through the forkhead box O3a pathway and promoted protein synthesis and myogenesis via reactivation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling. Molecular docking analysis further suggested that SQ potentially modulates PI3K activity by favorably occupying its regulatory pocket. In adipose tissue, SQ alleviated fat wasting by suppressing AMP-activated protein kinase phosphorylation, leading to reduced lipolysis and fat browning while enhancing adipogenic/lipogenic gene expression. Overall, these findings demonstrate that SQ mitigates cancer-induced muscle and adipose tissue wasting through modulation of catabolic signaling pathways, highlighting its potential as a nutritional intervention for cancer cachexia.