A novel FXYD5 / MTDH axis regulates the progression and immune response of ovarian cancer

Background Ovarian cancer still has a poor prognosis due to its rapid progression, resistance to chemotherapy, and poor response to immunotherapy. Dysadherin (FXYD5), a regulator of Na+/K+-ATPase, is implicated in ovarian cancer metastasis and chemotherapy resistance; however, its underlying mechanisms remain incompletely understood. Metadherin (MTDH), an oncoprotein associated with cancer metastasis, survival, and modulation of CD8+ T cell infiltration and immune responses in various malignancies, has also been characterized. Here, we accidentally identified a functional link between FXYD5 and MTDH. Methods Employing co-immunoprecipitation, wound healing assays, and tumor cell/CD8+ T cell co-culture systems, alongside analysis of public databases, we investigated the role of the novel FXYD5/MTDH axis in ovarian cancer prognosis and its mechanistic basis. Results Our findings demonstrate that FXYD5 stabilises the expression of the MTDH protein by inhibiting its ubiquitin-mediated degradation, thereby promoting tumour cell proliferation and migration. Furthermore, we have established that the FXYD5/MTDH axis upregulates PD-L1 expression, contributing to a poor response to immune checkpoint inhibitors. Taken together, these results reveal a novel mechanism underlying the poor prognosis associated with ovarian cancer. The FXYD5/MTDH axis may represent a potential prognostic biomarker and therapeutic target for ovarian cancer intervention.