Matrix stiffness-dependent PD-L2 deficiency improves SMYD3/xCT-mediated ferroptosis and the efficacy of anti-PD-1 in HCC
Introduction: Heterogeneous tissue stiffening promotes tumor progression and resistance, and predicts a poor clinical outcome in patients with hepatocellular carcinoma (HCC). Ferroptosis, a congenital tumor suppressive mechanism, mediates the anticancer activity of various tumor suppressors, includi...
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Elsevier
2025-07-01
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| Series: | Journal of Advanced Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2090123224003631 |
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| author | Shunxi Wang Xiaoxue Yuan Zetao Yang Xuan Zhang Zhiling Xu Li Yang Xian Yang Wei Zhou Wanqian Liu |
| author_facet | Shunxi Wang Xiaoxue Yuan Zetao Yang Xuan Zhang Zhiling Xu Li Yang Xian Yang Wei Zhou Wanqian Liu |
| author_sort | Shunxi Wang |
| collection | DOAJ |
| description | Introduction: Heterogeneous tissue stiffening promotes tumor progression and resistance, and predicts a poor clinical outcome in patients with hepatocellular carcinoma (HCC). Ferroptosis, a congenital tumor suppressive mechanism, mediates the anticancer activity of various tumor suppressors, including immune checkpoint inhibitors, and its induction is currently considered a promising treatment strategy. However, the role of extracellular matrix (ECM) stiffness in regulating ferroptosis and ferroptosis-targeted resistance in HCC remains unclear. Objectives: This research aimed to explore how extracellular matrix stiffness affects ferroptosis and its treatment efficacy in HCC. Methods: Ferroptosis analysis was confirmed via cell activity, intracellular ferrous irons, and mitochondrial pathology assays. Baseline PD-L2, SMYD3, and SLC7A11 (xCT) were evaluated in 67 sorafenib-treated patients with HCC (46 for non-responder and 21 for responder) from public data. The combined efficacy of shPD-L2, sorafenib, and anti-PD-1 antibody in HCC was investigated in vivo. Results: Here, we revealed that matrix stiffness-induced PD-L2 functions as a suppressor of xCT-mediated ferroptosis to promote cancer growth and sorafenib resistance in patients with HCC. Mechanically, matrix stiffening induced the expression of PD-L2 by activating SMYD3/H3K4me3, which acts as an RNA binding protein to enhance the mRNA stability of FTL and elevate its protein level. Knockdown of PD-L2 significantly promoted xCT-mediated ferroptosis induced by RSL3 or sorafenib on stiff substrate via FTL, whereas its overexpression abolished these upward trends. Notably, PD-L2 deletion in combination with sorafenib and anti-PD-1 antibody significantly sensitized HCC cells and blunted cancer growth in vivo. Additionally, we found the ferroptosis- and immune checkpoint-related prognostic genes that combined PD-L2, SLC7A11 and SYMD3 well predict the clinical efficacy of sorafenib in patients with HCC. Conclusion: These findings expand our understanding of the mechanics-dependent PD-L2 role in ferroptosis, cancer progression and resistance, providing a basis for the clinical translation of PD-L2 as a therapeutic target or diagnostic biomarker. |
| format | Article |
| id | doaj-art-e66559312ebb4e0d8f05945e65dce14c |
| institution | Kabale University |
| issn | 2090-1232 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Advanced Research |
| spelling | doaj-art-e66559312ebb4e0d8f05945e65dce14c2025-08-20T03:47:16ZengElsevierJournal of Advanced Research2090-12322025-07-017326528210.1016/j.jare.2024.08.021Matrix stiffness-dependent PD-L2 deficiency improves SMYD3/xCT-mediated ferroptosis and the efficacy of anti-PD-1 in HCCShunxi Wang0Xiaoxue Yuan1Zetao Yang2Xuan Zhang3Zhiling Xu4Li Yang5Xian Yang6Wei Zhou7Wanqian Liu8Key Laboratory of Biorheological Science and Technology, Ministry of Education& 111 Project Laboratory of Biomechanics and Tissue Repair, Bioengineering College, Chongqing University, Chongqing 400044, ChinaKey Laboratory of Biorheological Science and Technology, Ministry of Education& 111 Project Laboratory of Biomechanics and Tissue Repair, Bioengineering College, Chongqing University, Chongqing 400044, ChinaKey Laboratory of Biorheological Science and Technology, Ministry of Education& 111 Project Laboratory of Biomechanics and Tissue Repair, Bioengineering College, Chongqing University, Chongqing 400044, ChinaKey Laboratory of Biorheological Science and Technology, Ministry of Education& 111 Project Laboratory of Biomechanics and Tissue Repair, Bioengineering College, Chongqing University, Chongqing 400044, ChinaKey Laboratory of Biorheological Science and Technology, Ministry of Education& 111 Project Laboratory of Biomechanics and Tissue Repair, Bioengineering College, Chongqing University, Chongqing 400044, ChinaKey Laboratory of Biorheological Science and Technology, Ministry of Education& 111 Project Laboratory of Biomechanics and Tissue Repair, Bioengineering College, Chongqing University, Chongqing 400044, ChinaKey Laboratory of Biorheological Science and Technology, Ministry of Education& 111 Project Laboratory of Biomechanics and Tissue Repair, Bioengineering College, Chongqing University, Chongqing 400044, ChinaChongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing 400030, China; Department of Radiation Oncology, Chongqing University Cancer Hospital, Chongqing, China; Corresponding author at: Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing 400030, China.Key Laboratory of Biorheological Science and Technology, Ministry of Education& 111 Project Laboratory of Biomechanics and Tissue Repair, Bioengineering College, Chongqing University, Chongqing 400044, China; Corresponding author at: Bioengineering Institute of Chongqing University, 174 Shazheng Street, Chongqing 400044, China.Introduction: Heterogeneous tissue stiffening promotes tumor progression and resistance, and predicts a poor clinical outcome in patients with hepatocellular carcinoma (HCC). Ferroptosis, a congenital tumor suppressive mechanism, mediates the anticancer activity of various tumor suppressors, including immune checkpoint inhibitors, and its induction is currently considered a promising treatment strategy. However, the role of extracellular matrix (ECM) stiffness in regulating ferroptosis and ferroptosis-targeted resistance in HCC remains unclear. Objectives: This research aimed to explore how extracellular matrix stiffness affects ferroptosis and its treatment efficacy in HCC. Methods: Ferroptosis analysis was confirmed via cell activity, intracellular ferrous irons, and mitochondrial pathology assays. Baseline PD-L2, SMYD3, and SLC7A11 (xCT) were evaluated in 67 sorafenib-treated patients with HCC (46 for non-responder and 21 for responder) from public data. The combined efficacy of shPD-L2, sorafenib, and anti-PD-1 antibody in HCC was investigated in vivo. Results: Here, we revealed that matrix stiffness-induced PD-L2 functions as a suppressor of xCT-mediated ferroptosis to promote cancer growth and sorafenib resistance in patients with HCC. Mechanically, matrix stiffening induced the expression of PD-L2 by activating SMYD3/H3K4me3, which acts as an RNA binding protein to enhance the mRNA stability of FTL and elevate its protein level. Knockdown of PD-L2 significantly promoted xCT-mediated ferroptosis induced by RSL3 or sorafenib on stiff substrate via FTL, whereas its overexpression abolished these upward trends. Notably, PD-L2 deletion in combination with sorafenib and anti-PD-1 antibody significantly sensitized HCC cells and blunted cancer growth in vivo. Additionally, we found the ferroptosis- and immune checkpoint-related prognostic genes that combined PD-L2, SLC7A11 and SYMD3 well predict the clinical efficacy of sorafenib in patients with HCC. Conclusion: These findings expand our understanding of the mechanics-dependent PD-L2 role in ferroptosis, cancer progression and resistance, providing a basis for the clinical translation of PD-L2 as a therapeutic target or diagnostic biomarker.http://www.sciencedirect.com/science/article/pii/S2090123224003631Matrix stiffnessPD-L2FerroptosisSorafenib resistanceImmunotherapyHepatocellular carcinoma |
| spellingShingle | Shunxi Wang Xiaoxue Yuan Zetao Yang Xuan Zhang Zhiling Xu Li Yang Xian Yang Wei Zhou Wanqian Liu Matrix stiffness-dependent PD-L2 deficiency improves SMYD3/xCT-mediated ferroptosis and the efficacy of anti-PD-1 in HCC Journal of Advanced Research Matrix stiffness PD-L2 Ferroptosis Sorafenib resistance Immunotherapy Hepatocellular carcinoma |
| title | Matrix stiffness-dependent PD-L2 deficiency improves SMYD3/xCT-mediated ferroptosis and the efficacy of anti-PD-1 in HCC |
| title_full | Matrix stiffness-dependent PD-L2 deficiency improves SMYD3/xCT-mediated ferroptosis and the efficacy of anti-PD-1 in HCC |
| title_fullStr | Matrix stiffness-dependent PD-L2 deficiency improves SMYD3/xCT-mediated ferroptosis and the efficacy of anti-PD-1 in HCC |
| title_full_unstemmed | Matrix stiffness-dependent PD-L2 deficiency improves SMYD3/xCT-mediated ferroptosis and the efficacy of anti-PD-1 in HCC |
| title_short | Matrix stiffness-dependent PD-L2 deficiency improves SMYD3/xCT-mediated ferroptosis and the efficacy of anti-PD-1 in HCC |
| title_sort | matrix stiffness dependent pd l2 deficiency improves smyd3 xct mediated ferroptosis and the efficacy of anti pd 1 in hcc |
| topic | Matrix stiffness PD-L2 Ferroptosis Sorafenib resistance Immunotherapy Hepatocellular carcinoma |
| url | http://www.sciencedirect.com/science/article/pii/S2090123224003631 |
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