2. Academic Validation
  3. Thyroid Hormone Receptor β1 and PGC1α Coordinately Regulate OPA1/MFN2-Mediated Mitochondrial Fusion and UCP1-Mediated Lipid Browning in ccRCC

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

  • Adv Sci (Weinh). 2025 Nov 9:e08571. doi: 10.1002/advs.202508571.
Xiangui Meng 1 2 3,  Tiexi Yu 1 2 3,  Fang Lv 1 2 3,  Weiquan Li 1 2 3,  Hongmei Yang 4,  Xiaoping Zhang 1 2 3,  Wen Xiao 1 2 3
Affiliations

Affiliations

  • 1 Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
  • 2 Shenzhen Huazhong University of Science and Technology Research Institute, Shenzhen, 518000, China.
  • 3 Institute of Urology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
  • 4 Department of Pathogenic Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
PMID: 41208194 DOI: 10.1002/advs.202508571
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.

Keywords

ccRCC; lipid browning; mitochondrial fusion; the peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha (PGC1α); the thyroid hormone receptor β1 (TRβ).

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