Thyroid Hormone Receptor β1 and PGC1α Coordinately Regulate OPA1/MFN2‐Mediated Mitochondrial Fusion and UCP1‐Mediated Lipid Browning in ccRCC

Abstract The abnormal accumulation of lipids is a hallmark of clear cell renal cell carcinoma (ccRCC). Both the thyroid hormone receptor β1 (TRβ) and peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha (PGC1α) are key regulators of mitochondrial function and lipid metabolism. However, their specific interaction and influence on ccRCC development and lipid accumulation remain poorly understood. This study identified genes jointly regulated by TRβ and PGC1α, which are implicated in lipid browning and mitochondrial fusion. Mechanistically, T3‐activated TRβ interacts with PGC1α to transcriptionally upregulate PGC1α, UCP1, and mitochondrial fusion genes OPA1 and MFN2, thereby enhancing mitochondrial activity, promoting lipid utilization, and suppressing ccRCC progression. These results indicate that the mitochondrial and metabolic effects of TRβ in ccRCC are mediated through PGC1α expression and function. Activation of the TRβ/PGC1α through hormonal and pharmacological means may offer a promising therapeutic approach for ccRCC.