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<p>Radioresistance remains a major barrier to effective radiotherapy for liver hepatocellular carcinoma (LIHC). This study elucidates the molecular mechanism whereby astrocyte-elevated gene-1 (AEG-1/MTDH) modulates autophagy-driven radioresistance and evaluates its potential as a radiosensitization target. Bioinformatic analyses were performed using TCGA and CGGA datasets. Expression of key molecules was detected in 26 human LIHC specimens via qPCR, Western blot, and immunohistochemistry (IHC). Radioresistant SK-Hep-1R cells were established by fractionated irradiation. Lentiviral shRNA-mediated knockdown or plasmid-based overexpression, combined with pharmacologic autophagy inhibitors (3-MA, chloroquine), was used for functional studies. Co-immunoprecipitation (Co-IP), RNA immunoprecipitation (RIP), and actinomycin D chase assays were employed to characterize the MTDH–SND1–PTBP1–ATG5 axis. SK-Hep-1 xenograft-bearing BALB/c nude mice received single-dose 15 Gy radiotherapy in vivo. MTDH was significantly upregulated in LIHC tissues, correlating with advanced disease stage and poor radiotherapeutic response. Ionizing radiation induced MTDH expression in a time-dependent manner. MTDH silencing reduced clonogenic survival and increased apoptosis, while overexpression conferred radioresistance—effects abrogated by autophagy inhibition. Mechanistically, MTDH interacted with SND1 to recruit PTBP1, which directly binds ATG5 mRNA and extended its half-life, sustaining autophagic flux. Knockdown of MTDH or ATG5 mimicked autophagy blockade and sensitized cells to radiation. In xenografts, MTDH depletion synergized with radiotherapy to suppress tumor growth, decrease LC3-II levels, and enhance TUNEL positivity. The MTDH/SND1/PTBP1/ATG5 axis represents a novel post-transcriptional regulatory pathway that promotes LIHC radioresistance via protective autophagy. Targeting this network provides a rational approach to overcome radioresistance and improve LIHC radiotherapy outcomes.</p>

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AEG-1/MTDH Enhances Hepatocellular Carcinoma Radioresistance by Recruiting PTBP1 Via SND1 To Stabilize ATG5 mRNA and Promote Protective Autophagy

  • 期刊论文

  • 发表日期：

    2026年1月21日

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  • Xiaochun Chen,
  • Yu Wang,
  • Qishuai Guo,
  • Xing Lin,
  • Zhiping Yuan,
  • Wei Liu,
  • Chuan Lin,
  • Yongjun Li,
  • Yongpeng He

摘要

Radioresistance remains a major barrier to effective radiotherapy for liver hepatocellular carcinoma (LIHC). This study elucidates the molecular mechanism whereby astrocyte-elevated gene-1 (AEG-1/MTDH) modulates autophagy-driven radioresistance and evaluates its potential as a radiosensitization target. Bioinformatic analyses were performed using TCGA and CGGA datasets. Expression of key molecules was detected in 26 human LIHC specimens via qPCR, Western blot, and immunohistochemistry (IHC). Radioresistant SK-Hep-1R cells were established by fractionated irradiation. Lentiviral shRNA-mediated knockdown or plasmid-based overexpression, combined with pharmacologic autophagy inhibitors (3-MA, chloroquine), was used for functional studies. Co-immunoprecipitation (Co-IP), RNA immunoprecipitation (RIP), and actinomycin D chase assays were employed to characterize the MTDH–SND1–PTBP1–ATG5 axis. SK-Hep-1 xenograft-bearing BALB/c nude mice received single-dose 15 Gy radiotherapy in vivo. MTDH was significantly upregulated in LIHC tissues, correlating with advanced disease stage and poor radiotherapeutic response. Ionizing radiation induced MTDH expression in a time-dependent manner. MTDH silencing reduced clonogenic survival and increased apoptosis, while overexpression conferred radioresistance—effects abrogated by autophagy inhibition. Mechanistically, MTDH interacted with SND1 to recruit PTBP1, which directly binds ATG5 mRNA and extended its half-life, sustaining autophagic flux. Knockdown of MTDH or ATG5 mimicked autophagy blockade and sensitized cells to radiation. In xenografts, MTDH depletion synergized with radiotherapy to suppress tumor growth, decrease LC3-II levels, and enhance TUNEL positivity. The MTDH/SND1/PTBP1/ATG5 axis represents a novel post-transcriptional regulatory pathway that promotes LIHC radioresistance via protective autophagy. Targeting this network provides a rational approach to overcome radioresistance and improve LIHC radiotherapy outcomes.