KCNK3 coordinates adipocyte lipid storage and thermogenic shifts via AMPK, modulating a ferroptosis-permissive state

Fat deposition is a critical economic trait in pigs, intricately linked to meat quality and feed efficiency. Although the potassium channel KCNK3 is well-established as a key regulator of brown adipose tissue function in humans and mice, its role in porcine adipobiology and lipid metabolism remains poorly understood. This study identifies the two-pore potassium channel KCNK3 as a key mediator of porcine adipocyte differentiation and lipid accumulation via a previously unrecognized, ferroptosis-dependent mechanism, thereby revealing a novel link between ionic signaling and metabolic reprogramming. Using CRISPR-engineered porcine cell models combined with multi-omics approaches, we demonstrate that KCNK3 displays distinct expression patterns in adipose tissue that correlate with fat deposition phenotypes across swine breeds. Genetic disruption of KCNK3 markedly enhances thermogenic capacity while suppressing lipid accumulation, a process associated with AMPK and AKT pathway activation. Integrated transcriptomic and lipidomic analyses further demonstrate that KCNK3 deficiency promotes the pathological accumulation of polyunsaturated fatty acids alongside sphingolipid depletion, resulting in a lipid profile characteristic of a pro-ferroptotic state. Mechanistically, KCNK3 loss-of-function induces iron overload, reactive oxygen species burst, and glutathione depletion, culminating in key ferroptotic events, potentially mediated by the AMPK-p53-GPX4 signaling cascade. While our multi-omics data support this model, further functional studies are needed to fully establish causality. Our findings thus provide the first evidence for the ion channel-mediated coordination of adipocyte lipid metabolism with the ferroptotic process, uncover a species-divergent role for KCNK3 in promoting lipogenesis in swine in contrast to its thermogenic role in rodents, and implicate the evolutionarily conserved AMPK-p53-GPX4 regulatory axis in this context. These discoveries not only highlight KCNK3 as a potential target for precision breeding of lean swine varieties but also suggest novel therapeutic strategies for human metabolic disorders based on targeted adipose tissue remodeling.