2536 - Dual Role and Mechanism of SOCS6 In Radiosensitization of Lung Cancer and Protection Against Radiation-Induced Lung Injury

Purpose/Objective(s): Radiotherapy is central to managing thoracic malignancies, but its efficacy is limited by radioresistance and radiation-induced normal tissue damage. Existing radioprotective agents often paradoxically confer radioprotection on tumors as well, which severely limits their clinical utility.Building on our prior finding that SOCS6 radiosensitizes esophageal cancer, this study aims to further elucidates its dual role in radiosensitizing lung cancer and protecting against radiation-induced lung injury, as well as the underlying molecular mechanisms.

Materials/Methods:

Lentivirus-mediated SOCS6-overexpressing stable cell lines were established in A549 and Mel-12 cells. CCK-8 and colony formation assays were used to evaluate the radiosensitizing effect of SOCS6 and its protective effect. Lung cancer and lung injury models were subsequently established; tumor growth was monitored via in vivo imaging and caliper measurements every other day, and gene expression was assessed by H&E staining and immunohistochemistry. CT and blood analysis were performed to evaluate the protective role of SOCS6 against radiation-induced lung injury. Finally, proteomics and modification-specific sequencing, combined with IP-MS, were employed to identify downstream targets of SOCS6, and the underlying molecular mechanisms were further explored through CO-IP and ubiquitination assays.

Results:

In lung cancer cells, SOCS6 overexpression suppressed cell proliferation and reduced colony formation, indicating enhanced radiosensitization. In alveolar epithelial cells, SOCS6 knockout upregulated NLRP3, caspase-1, IL-18, and IL-1ß, while SOCS6 overexpression reversed these effects. In vivo, SOCS6 overexpression inhibited tumor growth in a xenograft mouse model and attenuated radiation-induced acute lung injury, accompanied by suppression of the inflammatory genes NLRP3, caspase-1, IL-18, and IL-1ß. Multi-omics analysis identified HSP60 as a SOCS6-interacting protein with increased ubiquitination and decreased expression upon SOCS6 overexpression. Co-immunoprecipitation and ubiquitination assays further demonstrated that SOCS6 binds HSP60 via its SOCS box and mediates its ubiquitination and degradation, thereby inhibiting NLRP3 inflammasome assembly and subsequent pyroptosis. These findings reveal a dual mechanism by which SOCS6 enhances radiosensitivity and mitigates radiation-induced lung injury.

Conclusion:

SOCS6 exerts dual radiosensitizing and lung injury-protective effects by mediating the ubiquitination and degradation of HSP60.