## 4 Discussion
### Drug Repurposing Based on Gene Signatures  
New chemotherapeutic drugs have advanced tumor treatment but their development process is expensive and time consuming. Also, not all developed drugs are effective in clinical trials. Thus, repurposing existing drugs may offer a quicker and more economical solution, as these drugs have already undergone safety testing and are used to treat other diseases [134; 135]. Among the upregulated hub genes, ziprasidone (ZIP) is the top candidate repurposed drug for ccRCC (Table 2). ZIP is an antipsychotic medication [136]. The effects of ZIP on inflammatory pathways like NF-kB and HIF-1 are not well established but studies found that it may inhibit several cancers such as pancreatic cancer [137] and breast cancer [138]. For instance, ZIP inhibits GOT1 to disrupt metabolic processes and reduce pancreatic cancer cell growth and has shown anti-cancer properties in xenograft models in preclinical studies [137]. Through in vitro studies, it was found that ZIP selectively inhibits aromatase with less toxicity than existing inhibitors in breast cancer [138]. Antipsychotic drugs such as haloperidol, chlorpromazine, thioridazine, and pendfuridol are now being studied for their potential anti-cancer properties [134]. Thioridazine has also been studied in the PI3K/AKT and NF-kB pathways [134; 139; 140; 141]. Thus, the findings suggest that ZIP could be repurposed as a potential treatment for ccRCC since it was already tested in other cancer treatments and may inhibit pathways where other antipsychotic drugs were already being studied. For downregulated hub genes, fentazac, a nonsteroidal anti-inflammatory drug (NSAID), was the top candidate drug that may be repurposed for ccRCC (Table 2). The connection of inflammation and cancer has led to interest in NSAIDs for cancer treatment. NSAIDs like aspirin, ibuprofen, diclofenac, celecoxib, tepoxalin, naproxen, and indomethacin have demonstrated anti-cancer properties, and some are already in clinical trials [142; 143; 144; 145; 146; 147; 148]. Fentiazac has not yet been documented for cancer treatment, particularly ccRCC, but it may be repurposed to target ccRCC by inhibiting COX-1 and COX-2 [149], like other NSAIDs studied for cancer drug repurposing. As a COX-1 inhibitor, it may also inhibit pathways associated with ccRCC, such as MAPK and NF-kB, targeting genes like _EGFR_, _MAPK1_, and BCL2 [150; 151]. These considerations suggest that fentazac could be a potential candidate for ccRCC treatment. Other drug candidates associated with upregulated hub genes are etazolate, trequinsin, dicyclovering, and decitabine. On the other hand, the candidates for downregulated hub genes are asenapine, KU-60019, Fr-180204, and niacin (Table 2). Neuroactive drugs such as etazolate (phosphodiesterase inhibitor) and asenapine (dopamine and serotonin receptor antagonist) may target ccRCC by the MAPK, PI3K/Akt, and HIF-1\(\alpha\) pathways [152; 153; 154]. Trequinsin, a phosphodieserase inhibitor, and dicycloverine (phosphodiesterase inhibitor) commonly used for gastrointestinal cramps [155] may reduce side effects. However, their relationship with ccRCC and other cancers has not been documented yet. Decitabine (DNA methyltransferase inhibitor) induces G2/M cell cycle arrest in ccRCC cells by inhibiting the p38/NF-\(\kappa\)B pathway [156]. EX-527 (a SIRT inhibitor) can be repurposed to impact sirtuin pathways [157; 158] that are associated with ccRCC. KU-60019 (an ATM kinase inhibitor) may improve cancer treatment by inhibiting DNA damage response and reducing AKT phosphorylation. Its ability to radiosentize cancer cells supports its potential [159]. Fr-180204 (a MAP kinase inhibitor) can disrupt MAPK pathways, while cefotiam, an antibiotic [160], and niacin, a vitamin B precursor [161], do not directly target ccRCC, but they may have indirect roles by affecting inflammation and metabolic processes related to ccRCC. These potential drug candidates may help manage symptoms and inhibit ccRCC through several pathways.