The miR-199a-5p/XIAP axis defines cisplatin response, apoptotic control and spatial remodelling in High-grade serous ovarian cancer

ABSTRACT High-grade serous ovarian cancer (HGSOC) remains a leading cause of gynecologic cancer mortality, driven largely by late diagnosis and the emergence of platinum resistance. A defining feature of resistant disease is the persistence of pro-survival signaling despite therapeutic stress, frequently converging on blockade of apoptotic execution. XIAP is a central inhibitor of caspase activation, and microRNAs are increasingly recognized as regulators of stress-response networks; however, the functional output of a given miRNA–target relationship can vary with cellular state and treatment context, limiting inference from bulk assays or single-condition measurements. Here, we interrogate the miR-199a-5p/XIAP axis as an apoptosis-linked regulatory module by integrating (i) evolutionary and structural support for miR-199a-5p engagement with the XIAP 3′UTR, (ii) functional perturbation across paired cisplatin-sensitive and cisplatin-resistant ovarian cancer models, and (iii) spatially resolved validation in human ovarian tissue using multiplex FISH/immunofluorescence. Across cell states, we find that miR-199a-5p does not behave as a fixed “repressor” of XIAP: in the sensitive context, miR-199a-5p is consistent with basal XIAP repression and aligns with facilitated cisplatin-associated apoptotic responses, whereas in the resistant state this coupling is attenuated and cisplatin exposure reshapes the apparent regulatory output, revealing a functional dissociation between XIAP abundance and apoptotic engagement. These observations support context-dependent rewiring of post-transcriptional control during acquired resistance. In FFPE human specimens, multiplex imaging identifies a tumor-associated spatial reorganization of this axis. Non-neoplastic ovary displays compartmental segregation with epithelial-enriched XIAP and relatively weak, stromal-skewed miR-199a-5p, while HGSOC disrupts this architecture with widespread miR-199a-5p, increased spatial convergence with XIAP, and a prominent perinuclear—occasionally nuclear—miR-199a-5p pattern absent from controls, supported by quantitative co-localization descriptors. Together, our results nominate a human HGSOC-associated spatial phenotype of the miR-199a-5p/XIAP axis and highlight spatially informed strategies for biomarker development and rational resensitization approaches in platinum-resistant disease.