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

Year: 2026
Type: article
Abstract: 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 drugaltered 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-PEGimproved 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.
DOI: 10.7150/ijbs.132234
Authors: Yang Yue, Changdong Zhou, Qingyu Li, Xiaochang Zhang, Hongjun Lin, Ming Niu, Aihong Zhang, Shuiqin Gong, Lijing Yang, Yuke Cui, Hong Chen, Xiaodan Cheng, Jiangbo Li, Qi He, Chenhui Wang, Jian Li, Wen Yang, Jian Bai, Jingqi Shi, Yanze Li, Xing Qin, Xiangmei Chen, Liang Guo, Shengqi Wang
Language: English
Subfield: Cancer Research
Open Access status: gold
Estimated APC paid: $1,337
OpenAlex ID: W7221435055
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