PEGylated nicotinamide mononucleotide targeted ferroptosis in acute kidney injury by suppressing FAR1 palmitoylation in an ACAA1-dependent manner.

Acute kidney injury (AKI) remains a major health concern globally, with ferroptosis being the most critical pathological change in proximal tubule cells (PTCs). However, no specific pharmacotherapies have been developed yet. Here, by combining databases (in vitro LINCS and in vivo MTDS) covering drug-altered gene profiles with ferroptosis-associated FerrDb, nicotinamide mononucleotide (NMN) was identified to target renal ferroptosis. Furthermore, PEGylation increased the preferential uptake of NMN in mice renal cortex, enhancing its alleviating effect on AKI. Through MALDI-MS-based spatially resolved metabolomics and SEAM analyses, NMN-PEG was found to augment peroxisomal function in PTCs via ACAA1, leading to increased β-oxidation of LCFAs and VLCFAs to mitigate ferroptosis and inflammation. Notably, ACAA1 also suppressed palmitoylation of FAR1 Cys111 to mediate NMN-PEG-improved lipid metabolism. Our study is the first to reveal the renal ferroptosis-targeting role of NMN-PEG and the underlying molecular mechanism, shedding new light on the development of novel AKI therapeutics.