Dual-targeting phytochemicals Ergosterol and Quercetagetin implicate steroid metabolism–associated pathways in lung and liver cancer models

Introduction Hormone-associated cancers use steroid metabolism to grow and avoid the immune system, while traditional treatments have to deal with drug resistance and systemic toxicity. Methods This study is mainly divided into two parts. First, screening natural active ingredients for anti-lung cancer and anti-liver cancer and their network pharmacology research. Second, target identification and clinical drug design of potential medicinal components focusing on hormone metabolic pathways. Results and Discussion We found that ergosterol and quercetagetin are dual-targeting phytochemicals that interfered with hormone metabolism in a potential contributing pathway through androgen receptor (AR) and estrogen receptor 1 (ESR1) and enzymes such as 3 β HSD/17 β HSD using network pharmacology, molecular docking, and SMRT sequencing. We used HepG2 and A549 cell lines to do mechanistic studies. Our in vivo results were confirmed by mouse models of Lewis lung carcinoma and H22 hepatoma. Ergosterol may stop 3 β -hydroxysteroid dehydrogenase (3 β HSD) from working, which stop the conversion of DHEA to androstenedione in HepG2 cells. Quercetagetin may affect 17 β -hydroxysteroid dehydrogenase (17 β HSD), which throw off the balance of estradiol and estrone in A549 cells. In vivo studies showed that quercetagetin significantly stopped splenomegaly and thymic atrophy (p < 0.001). Pharmacokinetic analysis showed that 8 out of 31 compounds met Lipinski’s criteria. ADMET testing showed that ergosterol had poor solubility (Log S = −6.91) and fully bound to plasma proteins. Quercetagetin didn't pass through membranes well and was sensitive to P-glycoprotein efflux. Tailored nanocarrier systems showed significant improvements in overcoming these limitations: Ergosterol’s solubility increased by 1,000 times, and quercetagetin’s P-gp substrate status was removed. Molecular dynamics simulations showed that drug-nanocarrier interactions were stable, with ergosterol showing very little change (RMSD <0.1 nm). Overall, these findings support a working mechanistic hypothesis and motivate nanodelivery strategies to improve the developability of these phytochemicals for further preclinical evaluation.