ArticleJournal of advanced research2025
Matrix stiffness-dependent PD-L2 deficiency improves SMYD3/xCT-mediated ferroptosis and the efficacy of anti-PD-1 in HCC.
Article in Journal of advanced research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed.
- Defect-Engineered BiOAdvanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- OTUD1-mediated deubiquitination stabilizes SLC7A11 to suppress ferroptosis in hepatocellular carcinoma.Cellular oncology (Dordrecht, Netherlands) · 2026Article
- Mitochondrial Carrier SLC25A13 Drives Ferroptosis Resistance and Immune Evasion via a STAT3-IFI6 Circuit in Breast Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Target FADS1-arachidonic acid-ferroptosis axis: A metabolic bridge linking matrix stiffness to PDAC stemness.Materials today. Bio · 2026Article
- Strategies to target PD-1/PD-L1 in the tumor microenvironment.Cellular oncology (Dordrecht, Netherlands) · 2026Review
- Ultrasound-driven mechanical immunomodulation enhances tumor treatment sensitivity: advances from tumor mechanical immunobiology to immunotherapy applications.Frontiers in immunology · 2026Review
- Mechanical Microenvironment in Tumor Immune Evasion: Bidirectional Regulation Between Matrix Stiffness and Immune Cells and Its Therapeutic Implications.International journal of biological sciences · 2026Review
- Extracellular matrix stiffness in hepatocellular carcinoma: mechanisms and targeted therapeutic strategies.Frontiers in immunology · 2026Review
- Post-Translational Modification Networks in Ferroptosis: Orchestrating Defense, Drug Resistance, and Therapeutic Opportunities in Hepatocellular Carcinoma.Journal of hepatocellular carcinoma · 2026Review
- The role of PD‑1/PD‑L1 axis in liver diseases.Clinical and experimental medicine · 2025Review
- Unraveling the role of the solute carrier family in hepatocellular carcinoma: mechanisms and therapeutic prospects.Cancer cell international · 2025Review
- Soil and Seed: Tumor Microenvironment Nurtures Immunotherapy Resistance and Renewal.International journal of molecular sciences · 2025Review
- Identification of matrix stiffness-related molecular subtypes in HCC via integrating multi-omics analysis and machine learning algorithms.Journal of translational medicine · 2025Article
- Histone Methyltransferase SETD1B Maintains Cancer Stem Cell Niche by Regulating the Crosstalk between CD24 and Surface Adhesion Molecules in Hepatocellular Carcinoma.International journal of biological sciences · 2025Article
- The dual role of SLC7A11 in tumor drug resistance: mechanisms, challenges, and therapeutic potential.American journal of cancer research · 2025Review
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Authors and funding
9 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
introductionHeterogeneous 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.
objectivesThis research aimed to explore how extracellular matrix stiffness affects ferroptosis and its treatment efficacy in HCC.
methodsFerroptosis 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.
resultsHere, 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.
conclusionThese 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.
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