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Hydrogen sulfide mediated persulfidation regulates homocysteine metabolism and enhances ferroptosis in non-small-cell lung cancer

ABSTRACT: Ferroptosis, a novel form of regulated cell death triggered by the iron-dependent peroxidation of phospholipids, offers promising penitential for cancer therapy. Hydrogen sulfide (H2S), an endogenous metabolite of the transsulfuration pathway, has been implicated in ferroptosis. However, the precise regulatory mechanisms remain elusive. In this study, we systematically investigated the role of exogenous hydrogen sulfide in ferroptosis regulation in non-small-cell lung cancer (NSCLC). We demonstrated that H2S sensitizes NSCLC to ferroptosis both in vitro and in vivo. Mechanistically, hydrogen sulfide persulfurates the 195th cysteine residue of S-adenosyl homocysteine hydrolase (SAHH), thus impeding the binding of SAHH to its substrate S-adenosyl homocysteine (SAH). Consequently, this inhibition reduces SAHH activity, leading to a decreased homocysteine level. This reduction in homocysteine subsequently results in diminished levels of cysteine and glutathione, particularly under conditions of cystine depletion, which collectively potentiate the occurrence of ferroptosis. Together, our findings unveil H2S as pivotal regulator for homocysteine metabolism, increasing the sensitivity of NSCLC to ferroptosis. Importantly, these findings highlight its potential therapeutic value for enhancing ferroptosis-based cancer therapies for NCSCLC.

ORGANISM(S): Homo Sapiens

SUBMITTER: Yongyou Zhang

PROVIDER: PXD047493 | iProX | Mon Dec 04 00:00:00 GMT 2023

REPOSITORIES: iProX

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Hydrogen sulfide-mediated persulfidation regulates homocysteine metabolism and enhances ferroptosis in non-small cell lung cancer.

Zheng Hualei H Chen Huidi H Cai Yunjie Y Shen Min M Li Xilin X Han Yi Y Deng Xusheng X Cao Hongjie H Liu Junjia J Li Hao H Liu Benchao B Li Ganlin G Wang Xindong X Chen Hui H Hou Jingjing J Lin Shu-Hai SH Zong Lili L Zhang Yongyou Y

Molecular cell 20240924 20

Hydrogen sulfide (H₂S), a metabolite of the transsulfuration pathway, has been implicated in ferroptosis, a unique form of cell death caused by lipid peroxidation. While the exact mechanisms controlling ferroptosis remain unclear, our study reveals that H₂S sensitizes human non-small cell lung cancer (NSCLC) cells to this process, particularly when cysteine levels are low. Combining H₂S with cystine depletion significantly enhances the effectiveness of ferroptosis-based cancer therapy. Mechanist ...[more]

PMID: 39321805

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Project description:Ferroptosis is a form of regulated cell death driven by lipid peroxidation of polyunsaturated fatty acids (PUFAs). Endogenous PUFAs are nonconjugated PUFAs and their peroxidation proceeds via the hydrogen-atom transfer (HAT) mechanism. We previously reported that lipids with conjugated double bonds undergo lipid peroxidation mostly via a different mechanism, peroxyl radical addition (PRA), and were much more readily oxidizable than nonconjugated ones. In this study, we aim to elucidate the effects of various unsaturated lipids in sensitizing ferroptosis. We found that while some peroxidation-reactive lipids, such as 7-dehydrocholesterol, vitamins D3 and A, and coenzyme Q10, suppress ferroptosis, both nonconjugated and conjugated PUFAs enhanced cell death induced by RSL3, a ferroptosis inducer. Importantly, we showed that conjugated linolenic acid (CLA 18:3) could act as a ferroptosis inducer by itself and conjugated linoleic acid (CLA 18:2) was more potent in sensitizing cells to RSL3-induced cell death than any nonconjugated PUFAs. We next sought to elucidate the mechanism underlying the different ferroptosis-inducing potency of conjugated and nonconjugated PUFAs. Lipidomics revealed that conjugated and nonconjugated PUFAs are incorporated into distinct cellular lipid species. Furthermore, the different peroxidation mechanisms predict the formation of higher levels of reactive electrophilic aldehydes from conjugated PUFAs than nonconjugated PUFAs, which was confirmed by aldehyde-trapping and mass spectrometry. RNA sequencing revealed that protein processing in the endoplasmic reticulum and proteasome are among the most significantly upregulated pathways in cells treated with CLA 18:3, suggesting increased ER stress and activation of unfolded protein response. Significantly, using click chemistry, we observed increased protein adduction by oxidized lipids in cells treated with an alkynylated CLA 18:2 probe. These results suggest that protein damage by lipid electrophiles is a key step in ferroptosis.

Dataset Information

Hydrogen sulfide mediated persulfidation regulates homocysteine metabolism and enhances ferroptosis in non-small-cell lung cancer

Publications

Hydrogen sulfide-mediated persulfidation regulates homocysteine metabolism and enhances ferroptosis in non-small cell lung cancer.

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