Bulk and single-cell transcriptomics identify tumor-specific epithelial PSAT1 as a ferroptosis-associated therapeutic...

Cervical cancer, the fourth most frequent malignancy in women worldwide, continues to be a major public health concern. Around 90% of high-grade cervical cancer cases are linked to infection with human papillomavirus (HPV). This phenotype, histologically, includes two major subtypes of cervical cancer: squamous cell carcinoma and adenocarcinoma. Drug resistance poses a major hurdle to treatment because it targets the apoptotic pathway. To overcome this, there is an urgent need for alternative routes to a curative strategy. Here, we focused on identifying non-apoptotic cell death pathways as a potential therapeutic option. Bulk RNA sequencing data for cervical cancer samples were obtained from the TCGA-CESC dataset. We combined gene set enrichment analysis, co-expression network analysis, and machine learning, which revealed ferroptosis as a key vulnerability at the bulk RNA level. Single-cell RNA sequencing data further confirmed the expression of ferroptosis-related components, including SCC and ADC. Subsequent analyses focused on identifying key regulators of the ferroptosis pathway. Further dissection of ferroptosis regulators and PSAT1 was prioritized as a prime translational target in adenocarcinoma compared with squamous cell carcinoma. To advance therapeutic translation, we applied AI-driven de novo compound generation to design a candidate drug targeting PSAT1. Additionally, molecular docking and molecular dynamics simulations identified GEN_42 as a putative PSAT1-binding compound. These findings nominate PSAT1 as a therapeutic vulnerability in cervical adenocarcinoma and GEN_42 as a computationally generated lead compound for further biological, cellular, and in vivo analyses to elucidate ferroptosis-induced cell death through modulation of PSAT1 function.