Cervical squamous cell carcinoma (CSCC) represents a significant global health concern among females. Identifying new biomarkers and therapeutic targets is pivotal for improving the prognosis of CSCC. This study investigates the prognostic relevance of CCZ1 in CSCC and elucidates its downstream pathways and targets using a combination of bioinformatics analysis and experimental validation. Transcriptomic analysis of 239 CSCC and 3 normal cervical samples from The Cancer Genome Atlas database reveals a marked upregulation of CCZ1 mRNA levels in CSCC, and elevated CCZ1 mRNA levels were associated with poor prognosis. Immunohistochemical analysis of clinical samples also confirmed these findings. Furthermore, functional assays, including Cell Counting Kit-8, colony formation, Transwell, and flow cytometry, elucidated the influence of CCZ1 on CSCC cell proliferation, migration, invasion, and cell cycle progression. Remarkably, CCZ1 knockdown suppressed CSCC progression both in vitro and in vivo. Mechanistically, CCZ1 knockdown downregulated MMP2 and MMP17 expression. Restoring MMP2 or MMP17 expression rescued phenotypic alterations induced by CCZ1 knockdown. Hence, CCZ1 promotes CSCC progression by upregulating MMP2 and MMP17 expression, emerging as a novel biomarker in CSCC and presenting potential as a therapeutic target in CSCC.

Background/Objectives: Ovarian cancer has the highest mortality among gynecological malignancies, with platinum resistance significantly contributing to poor prognosis. We aimed to develop a multimodal model (MMHC-OCPR) to predict platinum response and recurrence risk, enabling earlier personalized treatment and improved outcomes. Methods: This multicenter retrospective study included a combined cohort of 431 patients, comprising 1182 whole slide images (WSIs) curated from two independent datasets. The primary cohort consisted of 376 patients from the National Cancer Center (China), which was further partitioned into training, validation and internal test sets to ensure model development and evaluation. An additional external test cohort was incorporated using publicly available data from TCGA, enhancing the generalizability of our findings. We implemented a weakly supervised multiple instance learning framework to integrate histopathological imaging with clinicopathological variables, further strengthened by the incorporation of the transformer-based pretrained encoder UNI2-h, which enhanced the model’s predictive performance. Results: All patients in the primary cohort had pathology slides collected from primary ovarian tumors and metastatic tumor, along with clinical factors related to prognosis and treatment response. The baseline platinum response classifier using primary WSIs achieved an AUC of 0.896 in the internal test group and 0.876 in the external test group. Integration of metastatic WSIs and clinical data inputs yielded a superior AUC of 0.914 in the internal test set. The recurrence risk model demonstrated a C-index of 0.801, rising to 0.838 after multimodal enhancement. The model stratified patients into low-, intermediate- and high-risk groups with 2-year progression-free survival rates of 77.3%, 48.0% and 2.0%, respectively. Conclusions: Our model enables the early detection of platinum resistance, guiding timely treatment intensification. The recurrence risk stratification supports personalized management by identifying patients with favorable outcomes following surgery and chemotherapy, potentially sparing them from maintenance therapy to reduce associated toxicity, cost, and enhance quality of life.

Platinum resistance remains a major obstacle in ovarian cancer, yet whether abnormal glycolysis and lactate metabolism drive this phenotype through protein lactylation remains unclear. Here, we investigated the role of lactate-driven protein lactylation in platinum resistance and sought to identify the key effector event involved. Global protein lactylation was assessed by immunohistochemistry in tumor samples from 122 patients with high-grade serous ovarian cancer, and integrated proteomic and lactylomic analyses were performed in fresh frozen tumors from 12 patients, followed by validation in ovarian cancer cell models and functional assays. Platinum resistant ovarian cancer exhibited enhanced glycolysis, increased lactate accumulation, and elevated global protein lactylation, which was associated with platinum resistance and shorter progression free survival. Integrated lactylome profiling identified ZMYM2 K529 lactylation as a platinum resistance associated event, and ZMYM2 was upregulated in platinum resistant tissues and cells. Mechanistically, lactate promoted ZMYM2 K529 lactylation, suppressed ubiquitin–proteasome mediated degradation, and increased ZMYM2 stability and abundance. Functionally, ZMYM2 enhanced cisplatin tolerance, homologous recombination repair, and tolerance to DNA damaging treatments. However, both wild-type ZMYM2 and the K529R mutant restored platinum-resistant phenotypes in ZMYM2-knockdown cells, indicating that K529 lactylation primarily maintains ZMYM2 stability rather than directly determining its downstream pro-resistance activity. Collectively, these findings identify a glycolysis–lactate–ZMYM2 lactylation axis that promotes platinum resistance in ovarian cancer and highlight lactylation-dependent ZMYM2 stabilization as a potential therapeutic vulnerability.