Adrenocortical carcinoma survival gene HMMR was identified as being targeted by fluorouracil and epirubicin using a gene coexpression network-based drug repositioning strategy.

Adrenocortical carcinoma (ACC), with poor prognosis, is one of the most aggressive endocrine cancers. Surgery is the mainstay of treatment; nevertheless, chemotherapy is usually needed. Mitotane, the medication licenced for ACC, has had mixed results. Drug repositioning based on gene coexpression networks has proven to be an effective method of discovering potential cancer treatments. A total of 139 human specimens were examined, comprising 106 metastatic ACCs, 14 benign adrenocortical adenomas (ACAs), and 19 normal adrenal cortex tissues. Hub genes were identified using weighted correlation network analysis (WGCNA), and their differential expression was confirmed by microarrays and RNA sequencing. Hub genes were analyzed in more depth for enrichment, coexpression, and protein-protein interaction. Two phases of survival analysis were conducted considering sex. Hub gene expression was associated with TP53 mutations and cancer stage. Hub genes were evaluated using regression analysis. Hub genes were associated with immune cell infiltration. Network analysis identified transcription factors that regulate hub genes. Drug-gene interaction network analyses were performed to reposition existing drugs. WGCNA-PPI analysis revealed 31 hub genes, 11 of which were overexpressed by more than fourfold, as well as HMMR and UBE2T, which were novel genes. All hubs showed significant correlations with survival, tumor staging, and TP53 mutation status in ACC tissues. Women overexpressing CDK1, UBE2C, PCLAF, and CCNB1 were more likely to suffer catastrophic deaths than men. In terms of ACC diagnostic capacity, all hub genes had AUCs greater than 0.90, with TOP2A, CDK1, and CCNB1 having the highest values. All hub genes, except for THYMS and RACGAP1, were negatively correlated with M2 macrophages and CD8 + T cells infiltration. Hub genes were co-expressed and regulated by 21 DE-TFs expressed differently between ACC and normal tissues. Novel pharmaceuticals are represented by fifteen out of thirty-four medications directed at hub genes and DE-TFs. Paclitaxel and cisplatin were the central nodes within the drug-gene network. Multiple drugs target TYMS and TOP2A, making them both promising targets for ACC. Fluorouracil and epirubicin target HMMR novel hub gene. HMMR as a novel ACC hub gene targets by fluorouracil and epirubicin, but fluorouracil has advantageous. The reason for this is that M2 macrophages promote fluorouracil resistance, whereas tumors overexpressing the HMMR gene demonstrate a negative infiltration of macrophages. Hub genes, associated with ACC development and progression, have negative impacts on survival rates, particularly in women. Network analysis shows fluorouracil and epirubicin target the ACC novel hub gene, HMMR. Fluorouracil was more effective due to its impact on M2 macrophage infiltration.