mTORC2 Phosphorylation of GSDME-N Drives Cullin4B-Mediated Proteasomal Degradation to Suppress Pyroptosis and Confer Radioresistance in Small Cell Lung Cancer

  • Adv Sci (Weinh). 2026 May 27:e75844. doi: 10.1002/advs.75844.
Qing-Qing Xu  1  2  3  4 ,  Ci-Ming Sun  1  2  3 ,  Sui-Xian Zhang  1  2  3 ,  Rui Li  1  2  3 ,  Chen-Fei Wu  1  2  3 ,  Zai-Shan Lin  1  2  3 ,  Li Li  1  2  3 ,  Run-Zhe Chen  1  2  3 ,  Qi-Wen Li  1  2  3 ,  Yuan-Yuan Chen  1  2  3 ,  Xuan Li  1  2  3 ,  Ming Chen  1  2  3
Affiliations
  • 1. State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China.
  • 2. Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China.
  • 3. United Laboratory of Frontier Radiotherapy Technology of Sun Yat-Sen University & Chinese Academy of Sciences Ion Medical Technology Co, Guangzhou, Guangdong, P. R. China.
  • 4. VIP Region, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China.
PMID: 42199156 DOI: 10.1002/advs.75844
Abstract

Radioresistance is a main reason for treatment failure in patients with small cell lung Cancer (SCLC). Consequently, it is important to determine the key mechanism and explore effective strategies to prevent SCLC radioresistance. We use an unbiased CRISPR screen to identify GSDME, a member of the Gasdermin (GSDM) family, as a critical driver of radiosensitivity in SCLC. Furthermore, we identify mTORC2 facilitates SCLC radioresistance by inhibiting GSDME-N-mediated Pyroptosis. Mechanistically, mTORC2 phosphorylates GSDME-N at serine 114 (S114), promoting the recruitment of the CUL4B-RBBP4 E3 ubiquitin Ligase complex. This complex mediates K48-linked ubiquitination of GSDME-N at lysine 41 (K41), leading to its proteasomal degradation. Clinically, elevated mTORC2 is linked to an unfavorable prognosis in SCLC patients. The study reveals mTORC2 phosphorylates GSDME-N and promotes its Cullin4B-mediated proteasomal degradation to suppress Pyroptosis and drive radioresistance in SCLC.

Keywords
GSDME; mTORC2; pyroptosis; radioresistance; small cell lung cancer.
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