Role of the <scp>UHRF1</scp> – <scp>KLHL6</scp> – <scp>CORO2B</scp> axis in obesity‐related insulin resistance

BACKGROUND: Obesity-related insulin resistance (IR) involves mitochondrial dysfunction and ferroptosis dysregulation. Ubiquitin-like with PHD and RING finger domains 1 (UHRF1), an epigenetic regulator of DNA methylation, mediates crucial functions in disease progression, though its mechanisms in IR remain unclear. METHODS: Using murine IR models and tumor necrosis factor-α (TNF-α)-induced adipocyte systems, UHRF1's regulation of mitophagy and ferroptosis was assessed. Bioinformatics identified downstream targets Kelch-like protein 6 (KLHL6) and coronin 2B (CORO2B), prompting examination of the UHRF1-KLHL6-CORO2B axis in obesity-related IR. RESULTS: Obesity-related IR mice exhibited increased body weight, impaired glucose and insulin tolerance, adipose tissue inflammation, impaired mitophagy, and alterations in ferroptosis-related parameters, accompanied by reduced UHRF1 expression. In vitro, TNF-α-treated adipocytes showed decreased mitophagy, elevated oxidative stress, and changes consistent with ferroptosis, along with lower UHRF1 levels. UHRF1 overexpression was associated with changes in PINK1/Parkin-related markers, cell viability, oxidative stress indicators, ferroptosis-related parameters, and inflammatory responses. UHRF1 overexpression was associated with increased KLHL6 DNA methylation, decreased KLHL6 expression, and alterations in CORO2B ubiquitination. CONCLUSIONS: UHRF1 overexpression was associated with decreased KLHL6 expression, altered CORO2B ubiquitination, and changes in autophagy-, ferroptosis-, and inflammation-related markers. These results provide insights into potential pathogenic mechanisms and suggest that UHRF1, KLHL6, and CORO2B may serve as candidate targets for further investigation in obesity-related IR.