m6preQ0 reduces oxidative stress and alleviates glucose-induced lipid accumulation via insulin/IGF-1 signaling pathway in C. elegans.

Given the rising global prevalence of obesity and associated metabolic diseases, identifying novel regulators of metabolic homeostasis represents a crucial unmet public health challenge. m6preQ0, a naturally occurring modified nucleobase and precursor to m6preQ1, participates in diverse biological processes. However, its regulatory potential in obesity and other metabolic diseases remains largely unexplored. This study reveals that m6preQ0 possesses potent in vitro antioxidant activity and effectively mitigates oxidative stress in Caenorhabditis elegans. Furthermore, in a glucose-induced high-fat model, m6preQ0 significantly reduces lipid accumulation by approximately 33.75%. Notably, this lipid-lowering effect requires a conserved insulin/IGF-1 signaling (IIS) pathway. Mechanistically, m6preQ0 modulates antioxidant and lipid metabolism gene expression by inhibiting the IIS pathway, thereby coordinating the oxidative stress response and metabolic regulation. Specifically, m6preQ0 upregulates β-oxidation genes, such as cpt-2 and acs-2, while downregulating the glycerolipid synthesis gene mboa-1. Collectively, our findings position m6preQ0 as a promising therapeutic candidate for the management of obesity-related metabolic disorders.