<p>Chemotherapy resistance remains a major obstacle in cervical cancer (CC) treatment. Protein degradation systems, particularly F-box proteins, attracted growing interest in this context. However, the key regulators and their underlying mechanisms in CC remain poorly understood. This study aimed to investigate the functional significance and underlying mechanism of FBXO38 in cisplatin resistance and malignant phenotype of CC. Clinical samples were analyzed to assess the association between FBXO38 and clinicopathological features. Parental HeLa and SiHa cell lines, as well as their cisplatin-resistant sublines, were subjected to FBXO38 overexpression or knockdown. Cell viability, apoptosis, colony formation, tumorsphere ability, lysosomal and STING-related marker expressions were conducted to evaluate FBXO38’s function and potential regulation pathway. In vivo experiments were assessed using xenograft models. NH₄Cl was used for lysosomal inhibition. FBXO38 downregulation was correlated with poor differentiation, lymph node metastasis, and reduced cisplatin sensitivity in clinical samples. Cisplatin-resistant CC cells exhibited progressive FBXO38 loss, whereas FBXO38 reintroduction restored drug sensitivity and suppressed colony formation, induced apoptosis, and reduced cancer stem–like phenotypes. Conversely, FBXO38 silencing enhanced chemoresistance, stemness, and tumor-initiating capacity. In vivo, FBXO38 depletion enhanced tumor-initiating capacity, reduced cisplatin-induced tumor suppression and apoptosis. Furthermore, FBXO38 ablation promoted lysosome-dependent STING degradation, leading to attenuated signaling. Treatment with lysosomal inhibitors restored STING activation and reversed cisplatin resistance. FBXO38 functions as a tumor suppressor by maintaining cisplatin sensitivity in CC through regulation of the lysosome-dependent STING pathway. Targeting FBXO38 and its regulatory axis may represent a promising strategy to overcome treatment failure.</p>