LOXL4 drives radiotherapy resistance and immunosuppression in glioma by targeting SOCS3 for degradation to activate STAT3 signaling.

Radiotherapy (RT) resistance in glioma is closely linked to abnormal JAK/STAT signaling, but its upstream drivers are unclear. This study investigates the role of lysyl oxidase-like 4 (LOXL4) in this process. LOXL4 expression and its correlation with prognosis and immune infiltration were analyzed using TCGA and CGGA datasets. Stable RT-resistant glioma cell models were established. The functional role of LOXL4 in DNA repair, apoptosis, and pathway activity was assessed. Molecular mechanisms were explored via co-immunoprecipitation (Co-IP) and mass spectrometry. A brain-targeted LOXL4 siRNA nanodelivery system was developed and evaluated in an orthotopic glioma mouse model combined with RT. LOXL4 is upregulated in high-grade glioma and RT-resistant patients, correlating with poor survival. Mechanistically, LOXL4 promotes the ubiquitination and degradation of suppressor of cytokine signaling 3 (SOCS3). This relieves SOCS3-mediated inhibition of JAK2, leading to sustained STAT3 activation. Consequently, this axis enhances DNA damage repair, inhibits apoptosis, and fosters an immunosuppressive tumor microenvironment. The brain-targeted LOXL4 siRNA nanodelivery system synergized with RT, significantly prolonging survival in glioma-bearing mice. LOXL4 acts as a novel upstream regulator of the JAK/STAT pathway by degrading SOCS3, driving RT resistance and immune remodeling in glioma. Targeting the LOXL4-SOCS3-STAT3 axis with a nanodelivery system presents a promising radiosensitization strategy.