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LPCAT1-mediated membrane phospholipid remodelling promotes ferroptosis evasion and tumour growth

Nature Cell Biology (2024)Cite this article

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Abstract

The mechanisms underlying the dynamic remodelling of cellular membrane phospholipids to prevent phospholipid peroxidation-induced membrane damage and evade ferroptosis, a non-apoptotic form of cell death driven by iron-dependent lipid peroxidation, remain poorly understood. Here we show that lysophosphatidylcholine acyltransferase 1 (LPCAT1) plays a critical role in ferroptosis resistance by increasing membrane phospholipid saturation via the Lands cycle, thereby reducing membrane levels of polyunsaturated fatty acids, protecting cells from phospholipid peroxidation-induced membrane damage and inhibiting ferroptosis. Furthermore, the enhanced in vivo tumour-forming capability of tumour cells is closely associated with the upregulation of LPCAT1 and emergence of a ferroptosis-resistant state. Combining LPCAT1 inhibition with a ferroptosis inducer synergistically triggers ferroptosis and suppresses tumour growth. Therefore, our results unveil a plausible role for LPCAT1 in evading ferroptosis and suggest it as a promising target for clinical intervention in human cancer.

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Fig. 1: Persistent treatment with either RSL3 or erastin induces membrane phospholipid saturation.
Fig. 2: RSL3-/erastin-resistant cells preferentially incorporate SFA-PLs into their membranes.
Fig. 3: LPCAT1 increases the degree of membrane phospholipid saturation.
Fig. 4: Ablation of LPCAT1 sensitizes cells to ferroptosis.
Fig. 5: LPCAT1-mediated ferroptosis inhibition relies on exogenous and endogenous SFAs.
Fig. 6: LPCAT1 promotes tumour development by ferroptosis evasion.
Fig. 7: Inhibition of LPCAT1 suppresses tumour growth.

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Data availability

RNA-seq data that support the findings of this study have been deposited in the National Center for Biotechnology Information Sequence Read Archive with the accession code PRJNA987832. Clinical data were obtained from the The Cancer Genome Atlas database. The original western blot images have been provided and are publicly available. Source data are provided with this paper. All other data supporting the findings of this study are available from the corresponding author on reasonable request.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (grant numbers 82030078 and 82330082 to J.L., and U23A20455 to L.S.), the Shenzhen Medical Research Fund (grant number B2302046 to J.L.), the National Key Research and Development Program of China (grant number 2020YFA0509400 to L.S.) and the Fundamental Research Funds for the Central Universities (grant number 23ykcxqt001 to J.L.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Author information

Author notes

  1. These authors contributed equally: Ziwen Li, Yameng Hu, Haiqing Zheng.

Authors and Affiliations

  1. Key Laboratory of Liver Disease of Guangdong Province, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

    Ziwen Li, Haiqing Zheng & Jun Li

  2. Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China

    Ziwen Li, Man Li, Yuanji Liu, Rongni Feng, Xincheng Li, Shuxia Zhang, Miaoling Tang, Meisongzhu Yang, Ruyuan Yu, Yingru Xu, Xinyi Liao, Suwen Chen, Wanying Qian, Qiliang Zhang & Jun Li

  3. Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China

    Yameng Hu

  4. Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA

    Daolin Tang

  5. Department of Biochemistry and Molecular Biology, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China

    Bo Li

  6. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China

    Libing Song & Jun Li

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Contributions

Project planning was done by J.L. and Z.L. Z.L., Y.H. and H.Z. performed most experiments, analysed data and wrote the paper. M.L., Y.L., R.F., M.Y. and X. Li. performed the animal experiments. S.Z., M.T., X. Liao, R.Y. and Y.X. performed the cell biology experiments. S.C., W.Q. and Q.Z. performed the lipidomic analyses. D.T. discussed experiments and edited the manuscript. B.L., L.S. and J.L. conceived the idea, designed and discussed experiments, supervised progress and extensively edited and communicated regarding the manuscript.

Corresponding authors

Correspondence to Bo Li, Libing Song or Jun Li.

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Extended data

Extended Data Fig. 1 Persistent RSL3 or erastin induces membrane PL saturation.

a, Viability analysis of the indicated cells treated with RSL3 or erastin. b–e, Relative cellular levels of GSH (b, d), DCFH-DA (c), and Ferro-Orange (e) were examined in the indicated RSL3- or erastin-treated cells. f, IB analysis of GPX4, FSP1, GCH1, DHODH, LPCAT3 and ACSL4 expression in the indicated cells. GAPDH served as a loading control. Data are presented as mean ± SD, n = 3 biologically independent samples in a, f, n = 6 biologically independent samples in b-e. Statistical analysis was performed using one-way ANOVA followed by Dunnett’s test in b-e, two-way ANOVA followed by Tukey’s test in a. NS, not significant.

Source data

Extended Data Fig. 2 The PL composition is rapidly modulated by extracellular FFAs.

a–h, Volcano plots of lipidomics analysis of the indicated cells treated with PA (5 μM, 10 h), or OA (5 μM, 10 h), or ALA (5 μM, 10 h), or AA (5 μM, 10 h). Cutoff: FC threshold = 2, P < 0.05. i-j, Volcano plots of lipidomics analysis of the indicated cells treated with mixed PA (5 μM, 10 h), OA (5 μM, 10 h), ALA (5 μM, 10 h), and AA (5 μM, 10 h). Cutoff: FC threshold = 2, P < 0.05. Data are presented as mean ± SD, n = 3 biologically independent samples in a-j. Statistical analysis was performed using an unpaired two-tailed Student’s t-test in a-j.

Extended Data Fig. 3 RSL3-/erastin-resistant cells prefer SFA into membrane PL.

a, Heatmaps showing the metabolite content as detected by metabolomics. b–d, Representative images (b, c) and quantification (d) of membrane azide-fluor 488 fluorescence intensity in the indicated cells treated with PA-alkyne (5 μM, 10 h), or AA-alkyne (5 μM, 10 h), or ALA-alkyne (5 μM, 10 h), or AA-alkyne (5 μM, 10 h) normalized against integrin β1 fluorescence intensity. Scale bar, 10 μm or 2 μm. e-g, Quantification of RSL3- or erastin-induced membrane Liperfluo fluorescence intensity in the indicated cells treated with different FAs normalized against Dil intensity. h, Viability analysis of the indicated cells treated with different FFAs plus RSL3 or erastin for 24h. Data are presented as mean ± SD, n = 3 biologically independent samples in a, h, n = 6 biologically independent samples in b-g. Statistical analysis was performed using an unpaired two-tailed Student’s t-test in h, and one-way ANOVA followed by Dunnett’s test in d-h. NS, not significant.

Source data

Extended Data Fig. 4 LPCAT1 is upregulated in RSL3-/erastin-resistant cells.

a, Quantitative real-time (RT)-PCR analysis of expression of LPCAT1, ATRX, SPAG4, FGF2, MTMR11, S100A16, CD68, HSF4, TCIRG1, and UPP1 in the cells transfected with the corresponding siRNA. b, IB analysis of LPCAT1 expression in the indicated cells. GAPDH served as a loading control. c, Heatmaps showing the integration of FFA-alkyne into the membrane of the indicated cells. d, e, Scatter plots showing the changes in levels of phospholipids in the indicated cells vs. parental cells. FC, fold change. Cutoff: FC threshold = 2, P < 0.05. f–i, Repartition (left) and levels (right) of SFA, MUFA, and PUFA in phospholipids in the indicated cells. j, Representative images (left) and quantification (right) of membrane azide-fluor 488 fluorescence intensity in the indicated cells treated with PA-alkyne (5 μM, 10 h) or AA-alkyne (5 μM, 10 h) normalized against integrin β1 fluorescence intensity. Scale bar, 10 μm or 2 μm. Data are presented as mean ± SD, n = 3 biologically independent samples in a-i, n = 6 biologically independent samples in j. Statistical analysis was performed using an unpaired two-tailed Student’s t-test in d-i, one-way ANOVA followed by Dunnett’s test in a, j. NS, not significant.

Source data

Extended Data Fig. 5 LPCAT1 increases the degree of saturation of membrane PL.

a, Representative images of membrane azide-fluor 488 and integrin β1 fluorescence intensity in the indicated cells treated with ALA-alkyne (5 μM, 10 h) or OA-alkyne (5 μM, 10 h) normalized against integrin β1 fluorescence intensity. Scale bar, 10 μm or 2 μm. b-c, Quantification of membrane azide-fluor 488 fluorescence intensity in the indicated cells treated with PA-alkyne (5 μM, 10 h), or OA-alkyne (5 μM, 10 h), or ALA-alkyne (5 μM, 10 h), or AA-alkyne (5 μM, 10 h) normalized against integrin β1 fluorescence intensity. d-f, Relative membrane PA-488 intensity was examined in RSL3 or erastin-treated cells at the indicated times normalized against integrin β1 fluorescence intensity. Data are presented as mean ± SD, n = 6 biologically independent samples in a-f. Statistical analysis was performed using one-way ANOVA followed by Dunnett’s test in b-c. NS, not significant.

Source data

Extended Data Fig. 6 LPCAT1-mediated ferroptosis independent of other pathways.

a, Quantification of membrane Liperfluo fluorescence intensity in the indicated cells treated with RSL3 or erastin for 10 h normalized against Dil intensity. b, IB analysis of GPX4, FSP1, GCH1, DHODH, LPCAT3 and ACSL4 expression in the indicated cells. GAPDH served as a loading control. Protein quantified against controls, set as 1.0. c–h, Relative cellular levels of DCFH-DA (c, d), Ferro-Orange (e, f), and GSH (g, h) were examined in the indicated cells. Data are presented as mean ± SD, n = 3 biologically independent samples in b, n = 6 biologically independent samples in a and c-h. Statistical analysis was performed using an unpaired two-tailed Student’s t-test in a, d, f, h, one-way ANOVA followed by Dunnett’s test in c, e, g. NS, not significant.

Source data

Extended Data Fig. 7 Ablation of LPCAT1 sensitizes cells to ferroptosis.

a, b, Cell death was quantified by PI staining coupled with flow cytometry in the indicated cells treated with RSL3 or erastin for 24 h. c, d, Left: Viability analysis of the indicated cells treated with erastin for 24 h; Right: IB analysis of LPCAT1 expression in the indicated cells. GAPDH served as a loading control. e, Representative images of the indicated cells treated with erastin for 24 h. f, Transmission electron microscopy images showing mitochondrial crest in cells treated with erastin for 24 h. Scale bar, 400 nm (left) and 50 nm (right). g, h, Viability analysis of the cells treated with the indicated ferroptosis inducers. i-k, Viability analysis of the indicated cells treated with RSL3 or erastin plus the indicated cell death inhibitors. Data are presented as mean ± SD, n = 3 biologically independent samples in a-k. Statistical analysis was performed using one-way ANOVA followed by Dunnett’s test in a-b, g-k, and two-way ANOVA followed by Tukey’s test in c, d. NS, not significant.

Source data

Extended Data Fig. 8 LPCAT1 inhibits ferroptosis rely exogenous or endogenous SFA.

a-b, left: Viability analysis of the indicated cells treated with RSL3 for 24 h. Right: IB analysis of LPCAT1 and LPCAT3 expression in the indicated cells. GAPDH served as a loading control. c-d, Viability analysis of the indicated cells, which were pretreated with the indicated concentration of TOFA for 24 h, followed by treatment with erastin or erastin plus ferrostatin-1 for 24 h, in the DFBS medium. e, Viability analysis of the indicated cells, which were pretreated with the indicated concentration of CAY10566 for 24 h, followed by treatment with erastin or erastin plus ferrostatin-1 for 24 h, in the DFBS medium. f, Viability analysis of the indicated cells, which were pretreated with the indicated concentration of palmitic acid and TOFA for 24 h, followed by erastin treatment for 24 h, in the DFBS medium. g, IB analysis of LPCAT1 expression in the indicated cells. h–k, Effects of ferroptosis inducer erastin on the growth of 3D tumour spheroids formed by the indicated cells treated with vehicle or with PA (50 mM) at the indicated time. Data are presented as mean ± SD, n = 3 biologically independent samples in a-k. Statistical analysis was performed using one-way ANOVA followed by Dunnett’s test in c-f, h-k, and two-way ANOVA followed by Tukey’s test in a-b. NS, not significant.

Source data

Extended Data Fig. 9 LPCAT1 promotes tumour development by ferroptosis evasion.

a, IB analysis of LPCAT1 expression in the indicated cancer cells. GAPDH served as a loading control. Protein quantified against controls, set as 1.0. b, Viability analysis of the indicated cells treated with RSL3 for 24 h. c, Heatmaps showing the knockdown efficiency of LPCAT1 in the indicated cells. d, Viability analysis of the indicated cells treated with RSL3 for 24 h. e, Viability analysis of the indicated cells treated with IKE (2 μM) or IKE (2 μM) plus Fer-1 (4 μM) for 24 h. f–h, Upper: IB analysis of LPCAT1 expression in the indicated tumour cells. GAPDH served as a loading control. Lower: Tumour growth curves of the indicated xenografts. n = 5 animals per group. Data are presented as mean ± SD, n = 3 biologically independent samples in a-h. Statistical analysis was performed using one-way ANOVA followed by Dunnett’s test in b, e-h. NS, not significant.

Source data

Extended Data Fig. 10 Inhibition of LPCAT1 suppresses tumour growth.

a, Representative IHC images from the indicated xenograft tumours (Scale bar: 40 μM). b, Staining scores of LPCAT1 and cleaved-caspase 3. Data are presented as mean ± SD, n = 6 biologically independent samples in a-b. Statistical analysis was performed using a two-tailed Student’s t-test and one-way ANOVA followed by Dunnett’s test in b. NS, not significant.

Source data

Supplementary information

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Supplementary Table 1

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Li, Z., Hu, Y., Zheng, H. et al. LPCAT1-mediated membrane phospholipid remodelling promotes ferroptosis evasion and tumour growth. Nat Cell Biol (2024). https://doi.org/10.1038/s41556-024-01405-y

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