Jingxuan Zhou，Longyun Zhang，Tingjun Liu，Jiatong Sun，Yuxi Sun，Shaorong Gao，Kerong Shi

Abstract

Orchestrated cellular fate remodeling is integral to tissue repair/replenishment. Extrinsic cues can trigger a switch from self-renewal priming to differentiation initiation in stem cells. However, cell fate remodeling-based therapy and/or transplanting stem cells suffer from limitations of retention and/or low efficiency. The study found reprogramming fatty acid metabolic flux facilitated cell fate remodeling. Knockdown of Ehhadh, a bi-functional fatty acid oxidase, promotes somatic cell reprogramming into iPSCs, but inhibits ESCs differentiation. Mechanically, Ehhadh knockdown disrupts the mitochondrial homeostasis, resulting in structural damage and functional impairment, via impacting on the stability of mitochondrial inner membrane transporter TIMM23. Meanwhile, Ehhadh knockdown activates AMPK/ULK1 pathway, resulting in mitophagy. The mitochondrial fission/mitophagy inhibitor, Mdivi-1, significantly attenuated Ehhadh-knockdown-induced pluripotent protein expression, but enhanced the Ehhadh-knockdown-inhibited three germ layer markers expression, providing evidence of the mechanistic causality between Ehhadh modulation and mitophagy or cell fate remodeling. In conclusion, the fatty acid oxidase Ehhadh mediates cell fate remodeling via mitophagy. The Ehhadh→mitophagy→cell fate remodeling axis provides evidence for possible strategies of manipulating stem cell fate (stemness perpetuation or differentiation execution) by modulating of fatty acid oxidation efficiency and/or targeting on mitochondrial rejuvenation and reorganization pathways, shedding light on drug development, organ replenishment, stem cell therapy, breed production.

Paper Linkage:https://doi.org/10.1016/j.freeradbiomed.2026.02.046