ArticleAging cell2026
DNMT1 Regulates Testosterone Synthesis in Aged Rat Leydig Cells via FTO-Mediated HSP90AA1 m
Article in Aging cell, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Testosterone levels decline progressively with age from the third decade of life, impairing spermatogenesis and contributing to age-related disorders, underscoring the importance of enhancing endogenous testosterone production. DNA methyltransferase 1 (DNMT1) promotes testosterone synthesis in Leydig cells (LCs), yet the underlying mechanism remains unclear. Here, we found that DNMT1 expression is downregulated in aging rat testes and senescent LCs in vitro, correlating with reduced testosterone levels. Gain- and loss-of-function experiments confirmed that DNMT1 positively regulates testosterone synthesis and alleviates LC senescence, and that DNMT1 overexpression reverses the senescent phenotype and restores testosterone production. Mechanistically, RNA-seq of DNMT1-knockdown LCs identified FTO as a downstream target; DNMT1 suppresses FTO expression by promoting Fto promoter methylation. catRAPID prediction and RIP-qPCR validated Hsp90aa1 mRNA as a direct FTO substrate; FTO regulates HSP90AA1 expression through m
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