Through activating the TDP43/Raptor/p62/Keap1/NRF2 axis, the reduction of Chchd10 in response to energy surplus awakens the adaptive response, which potentiates adipogenesis and GSTA4‐mediated 4‐HNE clearance to combat obesity. Here, GSTA4 is linked to obesity due to melanocortin 4 receptor deficiency.