Ether-glycerophospholipids (ether-GPs), the ether bond- (- O -) containing glycerophospholipids are major components of brain lipidome. Ether-GPs play a crucial role in regulating neuronal function, and their deficiency has been implicated in many neurodegenerative diseases. However, how they are affected after traumatic brain injury (TBI) is not known. Our data demonstrate a significant decrease in ether-GPs abundance in the mouse cortex following controlled cortical impact (CCI) induced TBI. This is at least in part due to the impairment of peroxisomal ether-GP synthesis in the mouse brain after TBI. We detected dysregulation of peroxisomal ether-GPs synthesizing enzymes - glyceronephosphate-O-acyltransferase (GNPAT) and alkylglycerone phosphate synthase (AGPS) in the injured mouse brains. Our data demonstrate a significant decline in GNPAT level in the peroxisomal fraction and a marked accumulation of AGPS in the cytosol of mouse cortices after TBI. To restore ether-GPs level in the injured brain, we treated TBI mice with an ether-GP precursor - 1-O-octadecylglycerol (OAG) to bypass peroxisomal ether-GPs synthesizing steps. OAG partially restored the levels of several ether-GPs, attenuated inflammatory cytokine expression and improved their functional recovery after TBI. Taken together, our data demonstrate that decline in ether-GPs abundance after TBI is at least in part due to the impairment in peroxisomal ether-GPs synthesis and that restoration of ether-GPs by OAG treatment can improve TBI outcomes.

The electron transport chain is a signaling hub for hydrogen sulfide (H ₂ S) that serves both as a respiratory substrate and an inhibitor. While acute sulfide toxicity is well characterized, cellular adaptations to chronic H ₂ S, particularly microbially-derived sulfide exposure in colon, is poorly understood. We report that chronic, low-level H ₂ S exposure (4 to 20 µM) drives robust carbon sequestration in lipid droplets (LD) across several human cell lines, driven by a coordinated remodeling of redox and nucleotide metabolism. Specifically, H ₂ S-induced reductive shifts in nicotinamide adenine dinucleotide (NAD) and coenzyme Q (CoQ) pools are accompanied by glycerol-3-phosphate accumulation and cytidine triphosphate (CTP) depletion. Lipidomic analysis reveals increased neutral lipid synthesis and triacylglyceride accumulation concomitant with decreased CTP-dependent synthesis of membrane phospholipids. Mitochondrial expression of a water-generating NADH oxidase attenuates LD accumulation and spatially confines the origin of H ₂ S-induced reductive stress signaling to this compartment. Interestingly, LD abundance increases even after H ₂ S withdrawal, continuing over 48 h, during which time the reductively-shifted NAD and CoQ pools slowly reoxidize. Inhibition of fatty acid synthesis during sulfide exposure impairs cellular recovery of respiration. These findings establish an active role for LDs in stress response and reveal that lipid biogenesis is a strategy for countering H ₂ S-induced redox imbalance. The sulfide–LD–redox axis uncovered in this study has implications for understanding how gut-derived H ₂ S, shaped by diet and microbiome, can influence metabolic health.