Dopaminylation of endothelial TPI1 suppresses ferroptotic angiocrine signals to promote lung regeneration over fibrosis

Lungs can undergo facultative regeneration, but handicapped regeneration often leads to fibrosis. How microenvironmental cues coordinate lung regeneration via modulating cell death remains unknown. Here, we reveal that the neurotransmitter dopamine modifies the endothelial niche to suppress ferroptosis, promoting lung regeneration over fibrosis. A chemoproteomic approach shows that dopamine blocks ferroptosis in endothelial cells (ECs) via dopaminylating triosephosphate isomerase 1 (TPI1). Suppressing TPI1 dopaminylation in ECs triggers ferroptotic angiocrine signaling to aberrantly activate fibroblasts, leading to a transition from lung regeneration to fibrosis. Mechanistically, dopaminylation of glutamine (Q) 65 residue in TPI1 directionally enhances TPI1’s activity to convert dihydroxyacetone phosphate (DHAP) to glyceraldehyde 3-phosphate (GAP), directing ether phospholipid synthesis to glucose metabolism in regenerating lung ECs. This metabolic shift attenuates lipid peroxidation and blocks ferroptosis. Restoring TPI1 Q65 dopaminylation in an injured endothelial niche overturns ferroptosis to normalize pro-regenerative angiocrine function and alleviate lung fibrosis. Overall, dopaminylation of TPI1 balances lipid/glucose metabolism and suppresses pro-fibrotic ferroptosis in regenerating lungs. [Display omitted] •Dopaminylation of TPI1 in the endothelial niche maintains lung regeneration•TPI1 dopaminylation in endothelial cells suppresses ferroptotic angiocrine signals•Restoring TPI1 dopaminylation induces regenerative angiocrine cues to curb fibrosis•TPI1 Q65 dopaminylation normalizes phospholipid synthesis to block ferroptosis Mo et al. show that the neurotransmitter dopamine modifies the metabolic enzyme TPI1 in endothelial cells to maintain lung regeneration. Mechanistically, dopamine modification of TPI1 directs its activity from phospholipid synthesis to glucose metabolism. Therefore, dopamine-modified TPI1 attenuates lipid peroxidation to overturn ferroptotic angiocrine signals, promoting lung regeneration over fibrosis.