Protective functions of metformin in LPS-induced H9C2 injury by miR-497-5p/BTRC/IκBα axis-mediated NF-κB pathway activation.

Abstract

Sepsis is a life-threatening organ dysfunction syndrome triggered by infection and uncontrolled inflammatory responses, with sepsis-associated myocardial dysfunction being a leading cause of mortality and morbidity. Metformin, a widely prescribed antihyperglycemic drug, has shown emerging protective effects beyond glucose control. In this study, we investigated the protective role of metformin against LPS-induced injury and inflammation in H9C2 and AC16 cardiomyocytes and explored the underlying mechanisms. LPS stimulation significantly reduced cell viability, promoted apoptosis, and upregulated proinflammatory cytokines (TNFα, IL-6, and IL-1β) in H9C2 and AC16 cells. Metformin treatment markedly alleviated these effects, indicating its protective role against LPS-induced cytotoxicity and inflammation. Mechanistically, metformin significantly upregulated microRNA miR-497-5p, which directly suppressed β-transducin repeat containing E3 ubiquitin-protein ligase (BTRC) expression, leading to inhibition of IκBα degradation and NF-κB pathway activation. Importantly, miR-497-5p knockdown or BTRC overexpression partially reversed the protective effects of metformin, restoring NF-κB signaling and inflammatory cytokine production. These findings collectively demonstrate that metformin protects H9C2 and AC16 cardiomyocytes from LPS-induced injury through miR-497-5p/BTRC axis-mediated suppression of NF-κB activation and highlight the functional importance of miR-497-5p and BTRC in this regulatory process. SIGNIFICANCE STATEMENT: This study highlights the protective effects of metformin against LPS-induced H9C2 and AC16 cell injury and inflammation, revealing a novel mechanism involving miR-497-5p/BTRC axis-mediated NF-κB pathway inhibition. These findings offer insights into potential therapeutic strategies for sepsis-associated myocardial dysfunction.