Metabolomic Analysis Identifies Betaine as a Key Mediator of TAp73α-Induced Ferroptosis in Ovarian Granulosa Cells

Granulosa cells (GCs) are essential for follicular growth and development, and their functional state critically impacts folliculogenesis. <i>TAp73α</i>, a transcriptionally active isoform of the <i>p73</i> gene, is crucial for maintaining follicular integrity. In this study, we demonstrate that <i>TAp73α</i> overexpression promotes ferroptosis in bovine GCs by downregulating <i>SLC7A11</i>, depleting intracellular glutathione (GSH), and enhancing lipid peroxidation, particularly under Erastin treatment. By contrast, <i>TAp73α</i> knockdown restores antioxidant capacity, elevates GSH levels, and attenuates ferroptosis. To elucidate the underlying mechanism, untargeted metabolomic profiling revealed that <i>TAp73α</i> overexpression significantly altered the metabolic landscape of GCs, with marked enrichment in the glutathione metabolism pathway. Notably, betaine-a metabolite closely linked to redox homeostasis-was markedly downregulated. Functional assays confirmed that exogenous betaine supplementation restored <i>SLC7A11</i> expression, increased GSH levels, and alleviated oxidative damage induced by either H₂O₂ or <i>TAp73α</i> overexpression. Moreover, betaine co-treatment effectively reversed lipid peroxide accumulation and mitigated <i>TAp73α</i>-induced ferroptosis. Collectively, our findings identify a novel mechanism by which <i>TAp73α</i> promotes ferroptosis in granulosa cells through the suppression of betaine and glutathione metabolism, highlighting betaine as a key metabolic modulator with promising protective potential.