HPV18-E7 stabilizes HSPA5 to preserve GPX4-dependent redox defense in cervical cancer.

Abstract

Cervical cancer remains a major cause of cancer-related morbidity and mortality in women worldwide. Although HPV18-positive tumors are frequently associated with aggressive clinicopathological behavior, the redox-linked mechanisms by which HPV18 drives cervical cancer progression remain incompletely defined. Here, integrated clinical, multi-omics, biochemical, and in vivo analyses were performed to delineate the role of HPV18-E7 in ferroptosis regulation. In the TCGA-CESC cohort, HPV18 positivity was associated with inferior progression-free survival and disease-free survival and was enriched in adenocarcinoma-related histology. Functionally, HPV18-E7 promoted cervical cancer cell proliferation and suppressed RSL3-induced ferroptotic death, lipid peroxidation, ferrous iron accumulation, and clonogenic loss. Integrated transcriptomic, proteomic, and metabolomic profiling identified ferroptosis defense, oxidative phosphorylation, glutathione/redox homeostasis, sulfur amino acid metabolism, and lipid remodeling as convergent pathways downstream of HPV18-E7. A lipid-focused re-analysis identified 41 features that met VIP > 1 and P < 0.05 in both knockdown comparisons and changed concordantly, of which 20 also met q < 0.05 in both comparisons. Reciprocal co-immunoprecipitation confirmed associations of HPV18-E7 with HSPA5 and of HSPA5 with GPX4. HPV18-E7 stabilized HSPA5 protein by attenuating K48-linked ubiquitination and proteasomal turnover, and thereby maintained GPX4 abundance. MG132, but not chloroquine under the tested condition, attenuated the loss of the HSPA5/GPX4 module after HPV18-E7 depletion, supporting a predominant proteasomal contribution in this setting. Gain- and loss-of-function rescue experiments established HSPA5 as a required downstream effector of HPV18-E7-mediated GPX4 maintenance and ferroptosis resistance. In a HeLa xenograft model, HPV18-E7 depletion markedly enhanced the antitumor efficacy of the ferroptosis inducer RSL3, accompanied by increased MDA and 4-HNE signals and reduced Ki67 and SCD1 expression. Collectively, these findings identify an HPV18-E7/HSPA5/GPX4 axis that promotes cervical cancer progression by preserving ferroptosis resistance, while lipid remodeling provides a complementary metabolic component of the phenotype.