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SCRN1 confers hepatocellular carcinoma resistance to ferroptosis by stabilizing GPX4 via STK38-mediated phosphorylation

Nature Cancer (2025)Cite this article

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Abstract

Systemic therapy is the optimal choice for individuals with unresectable or advanced hepatocellular carcinoma (HCC). However its effectiveness is constrained by resistance. Ferroptosis is a unique form of regulated cell death and plays an essential role in HCC systemic therapy. Here we identified that secernin-1 (SCRN1) was closely associated with ferroptosis resistance and poor prognosis in HCC. Specifically, high expression of SCRN1 enhances the interaction of phosphokinase serine/threonine kinase 38 (STK38) and glutathione peroxidase 4 (GPX4) to promote the phosphorylation of GPX4 at S45. This phosphorylation impairs heat shock protein family A member 8 (HSC70) recognition and degradation of GPX4 by chaperone-mediated autophagy, which further alleviates lipid peroxidation and ferroptosis. Our findings reveal a critical mechanism by which tumor cells antagonize ferroptosis through enhanced GPX4 phosphorylation and provide potential targets and strategies for HCC treatment.

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Fig. 1: SCRN1 is associated with sorafenib resistance and unfavorable prognosis in individuals with HCC.
Fig. 2: SCRN1 promotes sorafenib resistance in HCC.
Fig. 3: SCRN1 enhances tumor resistance to ferroptosis.
Fig. 4: SCRN1 suppresses ferroptosis by targeting GPX4.
Fig. 5: SCRN1 inhibits degradation of GPX4 by CMA.
Fig. 6: SCRN1 stabilizes GPX4 by promoting S45 phosphorylation.
Fig. 7: STK38 is responsible for SCRN1-mediated GPX4 phosphorylation.
Fig. 8: GPX4 phosphorylation correlates with sorafenib resistance.

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Data availability

The RNA-seq data that support the findings of this study have been deposited in the Gene Expression Omnibus under accession code GSE248764. Proteomics data have been deposited in the iProX database under accession code PXD047686. Data for GSEAs were obtained from FerrDb V2 (https://doi.org/10.1093/nar/gkac935). Human HCC genomic data were derived from TCGA Research Network at http://cancergenome.nih.gov/. 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

Code availability

No custom code was generated for this study.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81871253, 82071789, 82371782, 82101854 and 32400760), Shanghai Science and Technology Committee (18411951300), Shanghai Industrial Collaborative Innovation Project (HCXBCY-2023-041), Teaching Achievement Cultivation Project of NMU (JPY2022A15) and Clinical Research Special Project of Shanghai Health Commission (20224Y0254).

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Author notes

  1. These authors contributed equally: Yijie Tao, Shulei Yin, Kai Wei, Liyuan Zhao.

Authors and Affiliations

  1. National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, China

    Yijie Tao, Shulei Yin, Liyuan Zhao, Yani Cui, Chunzhen Li, Panpan Hu, Shenhui Yin, Likun Cui, Yixian He, Shu Yu, Jie Chen, Shaoteng Lu, Guifang Qiu, Mengqi Song, Siqi Yang, Qianshan Hou, Yiquan Xue, Chen Qian, Sheng Xu, Yizhi Yu & Zui Zou

  2. School of Anesthesiology, Naval Medical University, Shanghai, China

    Yijie Tao, Yani Cui, Panpan Hu & Zui Zou

  3. Department of Anesthesiology, Shanghai Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China

    Kai Wei

  4. School of Traditional Chinese Medicine, Naval Medical University, Shanghai, China

    Yunyang Wu

  5. Department of Respiratory and Critical Care Medicine, Changzheng Hospital, Naval Medical University, Shanghai, China

    Yunyan Zhang

  6. Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, China

    Zui Zou

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  1. Yijie Tao
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Contributions

Z.Z., Y.Y. and S.X. designed and supervised the research. Y.T., Shulei Yin, K.W., L.Z., Y.C., Y.W., P.H., Shenhui Yin, L.C., Y.Z., S. Yu, J.C., G.Q., M.S. and S. Yang performed experiments. Y.T., K.W. and Y.H. collected clinical tumor tissue samples and performed analyses. C.Q. and Y.X. provided reagents. C.L., Y.W., S.L. and Q.H. performed bioinformatics analyses. Z.Z., Y.Y., S.X. and Y.T. analyzed data and wrote the paper. All authors read and approved the manuscript.

Corresponding authors

Correspondence to Sheng Xu, Yizhi Yu or Zui Zou.

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Nature Cancer thanks Nabil Djouder and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 SCRN1 is associated with sorafenib resistance and unfavorable prognosis in HCC patients.

a, IC50 of sorafenib in WT and SR HepG2 cells (n = 5 biological replicates). The HL of WT and SR group was -1.42 and -3.01 respectively. b, c, Heat map (b) and KEGG analysis (c) of DEGs in RNA-sequencing between WT and SR HepG2 cells (GSE248764). Data were analyzed by two-sided permutation test, and P values were adjusted using the Benjamini-Hochberg method (c). d, SCRN1 expression in HCC samples of different histologic and pathologic grade in the TCGA cohort (G1&G2: n = 233 patients, G3&G4:136 patients, Stage 1: n = 173 patients, Stage 2-4: n = 177 patients). The boxplot’s lower and upper edges represent the first and third quartiles, with the central axis indicating the median. The whiskers reach the minimum and maximum values. e, Proportion of relapse cases were analyzed by SCRN1 expression in cohort1. f, g, SCRN1 expression in HCC cells treated with hypoxic culture, LA, and inflammatory factors (IFN: interferon, TNF: tumor necrosis factor) (n = 3 biological replicates). Data presented as mean ± s.d. of three independent experiments (f, g) or mean ± s.e.m. (a, d, e). Statistical significance was determined by nonlinear regression (a), two-tailed unpaired Student’s t-test (d, f, g), or two-tailed chi-square test (e).

Source data

Extended Data Fig. 2 SCRN1 promotes sorafenib resistance in HCC.

a, b, Establishment of stably SCRN1 KO (a) and SCRN1 OE (b) HepG2 cells. c-f, Cell proliferation (c), migration (d), cell death (e) and cell cloning formation (f) of WT and SCRN1 KO HepG2 cells (n = 3 biological replicates). Gating strategies for proliferation and cell death were presented in the upper panels of corresponding figures (c, e). g-i, Cell viability (g) (n = 6 biological replicates), IC50 of sorafenib (h) (n = 5 biological replicates) and cell cloning formation (i) of WT and SCRN1 OE HepG2 cells. The HL of WT and SCRN1 OE group was -3.13 and -2.57 respectively (h). j, Representative image of HCC PDOs at day 7. k, Representative immunofluorescence staining of PDOs and paired HCC tissues. Alpha fetoprotein (AFP), cytokeratin 19 (CK19), epithelial cell adhesion molecule (EPCAM). l, The volume of subcutaneous tumors generated by WT and SCRN1 KO HepG2 cells. m, Establishment of stably SCRN1 KO Huh7 cells. n-p, WT and SCRN1 KO Huh7 cells were injected subcutaneously into nude mice. Sorafenib (30 mg/kg) gavage was given every other day. The volume (n, o) and weight (p) of subcutaneous tumors in indicated mice are shown (n = 5 male mice per group). The boxplot’s lower and upper edges represent the first and third quartiles, with the central axis indicating the median. The whiskers reach the minimum and maximum values. Data presented as mean ± s.d. of three independent experiments (c-e) or mean ± s.e.m. (g, h, n, p). Statistical significance was determined by two-tailed unpaired Student’s t-test (c-e, g, p), nonlinear regression (h) or two-way ANOVA (n).

Source data

Extended Data Fig. 3 SCRN1 enhances tumor resistance to ferroptosis.

a, Expression and phosphorylation of indicated molecules in WT and SCRN1 KO HepG2 cells after sorafenib treatment. b, Expression of indicated molecules in WT and SCRN1 KO HepG2 cells. c, Cell death of WT and SCRN1 KO HepG2 cells pre-treated with different cell death inhibitors and stimulated with sorafenib. d-f, Lipid peroxidation (d), C11-BODIPY fluorescence (e) and representative images of Fe2+ content (f) of WT and SCRN1 KO HepG2 cells stimulated with sorafenib (n = 3 biological replicates). Gating strategy for C11-BODIPY fluorescence was presented in the upper panels of corresponding figures (e). g, Establishment of stably SCRN1 OE Huh7 cells. h, i, Percentage of cell death (h) and C11-BODIPY fluorescence (i) of WT and SCRN1 OE Huh7 cells treated with sorafenib and erastin (n = 3 biological replicates). j, k, Percentage of cell death (j) and C11-BODIPY fluorescence (k) of Hep3B cells transfected with control or SCRN1 siRNA and treated as indicated (n = 3 biological replicates). l, Establishment of stably SCRN1 KO HT1080 and NIH3T3 cells. m-p, Percentage of cell death (m, o) and C11-BODIPY fluorescence (n, p) of WT and SCRN1 KO HT1080 and NIH3T3 cells treated with indicated FINs (n = 3 biological replicates). q, Establishment of stably SCRN1 OE HT1080 and NIH3T3 cells. r-u, Percentage of cell death (r, t) and C11-BODIPY fluorescence (s, u) of WT and SCRN1 OE HT1080 and NIH3T3 cells treated with sorafenib and erastin (n = 3 biological replicates). v-y, Percentage of cell death (v, x) and C11-BODIPY fluorescence (w, y) of HCT116 and SW480 cells transfected with control or SCRN1 siRNA and treated as indicated (n = 3 biological replicates). Data shown are representative of three independent experiments with similar results (a, b, g, l, q). Data presented as mean ± s.d. of three independent experiments and statistical significance was determined by two-tailed unpaired Student’s t-test (d, e, h-k, m-p, r-y).

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Extended Data Fig. 4 SCRN1 suppresses ferroptosis by targeting GPX4.

a, The mRNA expression of PTGS2, solute carrier family 7 member 11(SLC7A11), ACSL4, glutathione synthetase (GSS), glutamate cysteine ligase (GCLC), GPX4, ACSL1 and FTH1 in WT and SCRN1 KO HepG2 cells treated with sorafenib (n = 3 biological replicates). b, Endogenous GPX4 expression in SCRN1 KO HepG2 cells transfected with SCRN1-Myc for indicated hours. c, The interaction between GPX4-Flag and SCRN1-Myc in HEK293T cells was detected by co-IP analysis. d, The endogenous interaction of SCRN1 with ACSL1 and FTH1 in HepG2 cells. e, Confocal analysis of endogenous GPX4 distribution in HepG2 cells treated with sorafenib or not. f, g, Respective images (f) and analysis (g) of co-localization between GPX4 and SCRN1 truncations in HepG2 cells (n = 10 cells per group). h, Schematic structure and truncates of SCRN1 N truncation. i, Interaction between GPX4-Flag and SCRN1-Myc N truncations in HEK293T cells was detected by co-IP analysis. j, Percentage of cell death of WT and SCRN1 KO HepG2 cells pre-treated with 2 mM GSH-EE and 1 mM NAC and stimulated with sorafenib (n = 3 biological replicates). Data shown are representative of three independent experiments with similar results (b-d, i). Data presented as mean ± s.d. of three independent experiments (a, j) or mean ± s.e.m. (g). Statistical significance was determined by two-tailed unpaired Student’s t-test (a, g, j).

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Extended Data Fig. 5 SCRN1 inhibits CMA mediated degradation of GPX4.

a, Quantification of GPX4 protein level in HepG2 and Huh7 cells via ImageJ software (n = 3 biological replicates). b, Representative images (left) and analysis (right) of autophagic flux of mCherry-EGFP-GPX4 in WT and SR HepG2 cells treated with sorafenib or not (n = 10 cells per group). c, d, GPX4 expression in LAMP2A KO Huh7 (c) and ATG5 KO HepG2 (d) cells with SCRN1 knockdown or not. e, Percentage of cell death of WT and LAMP2A KO HepG2 cells with SCRN1 knockdown or not and treated with sorafenib (n = 3 biological replicates). f, GPX4 expression in HepG2 cells treated with 6-AN for indicated hours. g, Representative images (left) and analysis (right) of general CMA activity in HepG2 cells treated with LA, hypoxia, inflammation factors or serum starvation for 18 h (n = 10 cells per group). h, Representative images (left) and analysis (right) of general CMA activity in WT and SR HepG2 cells treated with sorafenib or serum starvation for 18 h (n = 10 cells per group). i, Representative images (left) and analysis (right) of general CMA activity in SS and SR PDOs treated with sorafenib for 18 h (n = 10 cells per group). j, Representative images (left) and analysis (right) of general CMA activity in WT and SCRN1 KO HepG2 cells treated with sorafenib for 18 h (n = 8 cells per group). k, LAMP2A, HSC70 and GAPDH expression in WT and SCRN1 KO HepG2 cells. l, Interaction between SCRN1-Myc, LAMP2A-V5 and HSC70-Flag in HEK293T cells was detected by co-IP analysis. Data shown are representative of three independent experiments with similar results (c, d, f, k, l). Data presented as mean ± s.d. of three independent experiments (a, e) or mean ± s.e.m. (b, g-j). Statistical significance was determined by two-tailed unpaired Student’s t-test (a, b, e, g-j).

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Extended Data Fig. 6 SCRN1 stabilizes GPX4 by promoting S45 phosphorylation.

a, Expression of WT and single lysine site mutated GPX4 in HEK293T cells transfected with SCRN1-Myc or control plasmid. b, The structure of GPX4 CMA-target motif (124NVKFD128) and S45 site. The structure of GPX4 was obtained from Protein Data Bank (pdb_00002gs3). c, Detection of the specificity of p-GPX4S45 antibody by ELISA. d, The mRNA expression of SCRN1 and GPX4 in SS and SR PDOs (n = 4 biological replicates). e, Establishment of stably GPX4 KO HepG2 cells. f, Percentage of cell death of WT and GPX4 KO HepG2 cells treated with sorafenib and erastin (n = 3 biological replicates). g, Percentage of cell death of WT and GPX4 KO HepG2 cells with GPX4 reconstitution and treated with sorafenib (n = 3 biological replicates). Data shown are representative of three independent experiments with similar results (a, e). Data presented as mean ± s.d. of three independent experiments and statistical significance was determined by two-tailed unpaired Student’s t-test (d, f, g).

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Extended Data Fig. 7 STK38 is responsible for SCRN1 mediated GPX4 phosphorylation.

a, Dot plot showing GPX4-interacting proteins by using mass spectrometry. b, c, GPX4-Flag expression in HEK293T (b) and Huh7 (c) cells transfected with increasing STK38-Myc. d, GPX4-Flag expression in HEK293T cells transfected with increasing RIOK1-Myc. e, Endogenous interaction between STK38 and GPX4 in Huh7 cells. f, The mRNA expression of GPX4 in HepG2 cells transfected with control or STK38 siRNA (n = 3 biological replicates). g, GPX4-Flag expression in HEK293T cells transfected with STK38-Myc and treated with Baf-A1. h, The interaction between GPX4-Flag and LAMP2A in HEK293T cells transfected with STK38-Myc or control plasmid and treated with staurosporine or not. i, WT or S45A mutated GPX4 expression in HEK293T cells transfected with STK38-Myc. j-m, Establishment of stably STK38 KO HepG2 (j), Huh7 (k), HT1080 (l) and NIH3T3 (m) cells. n-s, Percentage of cell death (n, p, r) and C11-BODIPY fluorescence (o, q, s) of WT and STK38 KO Huh7, HT1080 and NIH3T3 cells treated with indicated FINs (n = 3 biological replicates). Data shown are representative of three independent experiments with similar results (b-e, g-m). Data presented as mean ± s.d. of three independent experiments and statistical significance was determined by two-tailed unpaired Student’s t-test (f, n-s).

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Extended Data Fig. 8 SCRN1 promotes the interaction of STK38 and GPX4.

a, GPX4 expression in WT and STK38 KO Huh7 cells with SCRN1 knockdown or not. b, The efficiency of stable SCRN1 overexpression in control and STK38 KO cells. c, STK38 expression in WT and SCRN1 KO HepG2 cells. d, e, The interaction between full length and truncations of STK38-Flag and SCRN1-Myc in HEK293T cells was detected by co-IP analysis. f, The interaction of STK38-Flag and SCRN1-Myc N truncations in HEK293T cells was detected by co-IP analysis. g, The phosphorylation of YAP1-V5 and interaction of STK38-Flag and YAP1-V5 in HEK293T cells was detected by co-IP analysis. h, i, The phosphorylation of YAP1 by STK38 in PDOs (h) (n = 4 PDOs) and HCC tumors (i) (n = 6 HCC tumors) was detected by in vitro kinase assays. j, The mRNA expression of c-MYC, PPAT, LDHA, BCAT1 and NPM1 in HepG2 and Huh7 cells with STK38 knockdown or not (PPAT: phosphoribosyl pyrophosphate amidotransferase, LDHA: lactate dehydrogenase A, BCAT1: branched chain amino acid transaminase 1, NPM1: nucleophosmin 1) (n = 3 biological replicates). k, l, The protein level of c-MYC in WT and STK38 KO HepG2 (k) and Huh7 (l) cells. m, The luciferase activity of c-MYC in HepG2 and Huh7 cells transfected with STK38 or control plasmid (n = 3 biological replicates). n, The mechanism of SCRN1 promoting ferroptosis resistance through enhancing GPX4 phosphorylation and abolishing CMA degradation of it via STK38 (created by Biorender). Data shown are representative of three independent experiments with similar results (a-i, k, l). Data presented as mean ± s.d. of three independent experiments (j, m) or mean ± s.e.m. (h, i). Statistical significance was determined by two-tailed unpaired Student’s t-test (j, m) or two-tailed paired Student’s t-test (h, i).

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Extended Data Fig. 9 GPX4 phosphorylation correlated with sorafenib resistance.

a, b, Representative images (a) and analysis (b) of GPX4 protein detection using IHC assay in cohort1 (CR: n = 11 patients, PR: n = 26 patients, PD: n = 43 patients). c, Two-tailed spearman correlation analysis between SCRN1 and GPX4 expression in cohort1. The error bar represents a 95% CI. d, Percentage of cases were analyzed by GPX4 expression in cohort1. The P value refers to the comparison of non-responsive patients (PD) between the high- and low- GPX4 groups. e, f, Representative MRI images (e) and GPX4 protein expression (f) in cohort2 (CR: n = 7 patients, PR: n = 3 patients, SD: n = 7 patients, PD: n = 7 patients). g, Percentage of cases were analyzed by GPX4 expression in cohort2. The P value refers to the comparison of non-responsive patients (SD and PD) between the high- and low- GPX4 groups. Data presented as mean ± s.e.m. and statistical significance was determined by two-tailed unpaired Student’s t-test (b, f) or two-tailed chi-square test (d, g).

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Extended Data Fig. 10 Targeting SCRN1 and STK38 improves sorafenib efficacy.

a-c, STK38 expression (a), cell death (b) (n = 3 biological replicates) and C11-BODIPY fluorescence (c) (n = 3 biological replicates) of HepG2 cells treated with 17-AAG. d, Size distribution and encapsulation efficiency of LNPs. e-g, Analysis of efficacy (e), hepatotoxicity (f), nephrotoxicity and cardiotoxicity (g) of LNP siSTK38 in vivo (n = 3 male mice per group). h, H&E staining (left) and injury assessment (right) of the heart, kidney, liver, spleen and adrenal gland of mice intravenously injected with 1 nmol LNPs. i, IHC staining (left) and analysis (right) of MDA of the heart, kidney, liver, spleen and adrenal gland of mice intravenously injected with 1 nmol LNPs (n = 3 biological replicates). j, Efficacy of LNP siSCRN1 and LNP siSTK38 in vitro (n = 3 biological replicates). k, l, Cell viability of HepG2 (k) (n = 6 biological replicates), HCT116 and SW480 (l) (n = 4 biological replicates) cells pretreated with LNP siSCRN1 or LNP siSTK38 and stimulated with sorafenib. m, GPX4 KO HepG2 cells were injected subcutaneously into nude mice. Sorafenib (30 mg/kg) gavage and intravenous injection of LNPs was given every other day. The volume subcutaneous tumors in indicated mice are shown (n = 5 male mice per group). n, o, STK38 expression (n) and C11-BODIPY fluorescence (o) (n = 3 biological replicates) in HepG2 cells treated with MEKK2 inhibitors and sorafenib. Data shown are representative of three independent experiments with similar results (a, n). Data presented as mean ± s.d. of three independent experiments (b, c, e-g, j, o) or mean ± s.e.m. (k, l). Statistical significance was determined by two-tailed unpaired Student’s t-test (b, c, e-g, j-l, o).

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Supplementary information

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Tao, Y., Yin, S., Wei, K. et al. SCRN1 confers hepatocellular carcinoma resistance to ferroptosis by stabilizing GPX4 via STK38-mediated phosphorylation. Nat Cancer (2025). https://doi.org/10.1038/s43018-025-01061-7

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