Adipose-specific Kdm2a deficiency promotes ferroptosis-associated features and hypertrophic remodeling of adipocytes.

Appropriate adipose tissue deposition plays a critical role in regulating systemic energy metabolic homeostasis. Epigenetic mechanisms have emerged as critical modulators of these processes; however, the role of specific histone demethylases in adipocytes remain poorly understood. Here, we investigated the physiological function of lysine demethylase 2A (Kdm2a) in adipose tissue using adipocyte-specific Kdm2a knockout (Kdm2aFat KO) mice under normal and high-fat dietary conditions. Although Kdm2a deficiency reduced overall fat mass and partially protected against diet-induced weight gain, it paradoxically induced pronounced adipocyte hypertrophy, insulin resistance, impaired energy metabolism, and adipose tissue dysfunction. Integrated transcriptomic and functional analyses revealed that loss of Kdm2a is accompanied by ferroptosis-associated features in adipocytes, an iron-dependent form of regulated cell death driven by lipid peroxidation. Ferroptosis activation was linked to epigenetic dysregulation to oxidative damage and metabolic collapse. Collectively, our findings identify Kdm2a as a critical epigenetic guardian of adipocyte integrity and establish a previously unrecognized connection between adipocyte hypertrophic remodeling and ferroptosis-associated features in metabolic disease.