Targeting IL-1R1 and androgen receptor using natural compounds from Aconitum heterophyllum and Podophyllum hexandrum: an in silico and in vitro study

Background Lung and prostate cancers remain leading causes of cancer-related mortality worldwide, driven by inflammation-mediated tumour progression and hormone-dependent signalling. IL-1R1 promotes chronic inflammation, metastasis, and tumour survival, while androgen receptor (AR) signalling is a central driver of prostate cancer growth. Simultaneous targeting of inflammatory and androgenic pathways represents a promising strategy to overcome therapeutic resistance. Objectives This study aimed to evaluate natural compounds derived from Aconitum heterophyllum (atisine, linoleic acid) and Podophyllum hexandrum (podophyllotoxin), as modulators of IL-1R1 and AR using integrated experimental and computational approaches. Methods Phytochemicals were extracted from tuberous roots of A. heterophyllum and fruits of P. hexandrum using Soxhlet extraction and isolated by TLC and column chromatography. Cytotoxicity and long-term antiproliferative effects were assessed using MTT and colony formation assays in A549 (lung) and LNCaP (prostate) cancer cell lines. Computational analyses included ADMET profiling, molecular docking against IL-1R1 (PDB: 1ITB) and AR (PDB: 2YHD), 100 ns molecular dynamics simulations, MM-GBSA binding free-energy calculations, network pharmacology-based target and pathway enrichment analyses. Results Podophyllotoxin exhibited potent cytotoxicity with IC 50 values of 0.04 µM in both A549 and LNCaP cells, outperforming doxorubicin, while atisine showed moderate activity (IC 50 : 2.1–2.3 µM). Linoleic acid displayed weak anticancer activity (IC 50 >100 µM). Colony formation assays confirmed strong suppression of clonogenic survival by podophyllotoxin and a moderate inhibitory effect by atisine. Docking studies suggested favorable binding affinities (−8.1 to −5.9 kcal/mol), and molecular dynamics simulations demonstrated stable protein–ligand complexes with low RMSD fluctuations. ADMET analysis supported favorable drug-likeness for atisine and podophyllotoxin. Network pharmacology identified 133 intersecting targets, with key hub genes including SRC, EGFR, and AKT1, enriched in PI3K-Akt and cancer-related signaling pathways. Conclusion Atisine and podophyllotoxin exhibited significant anticancer activity and demonstrated favorable predicted interactions with the Interleukin-1 receptor type 1 (IL-1R1) and Androgen Receptor (AR), suggesting their potential as dual modulators that warrant further experimental validation. Their promising anticancer profile was supported by strong cytotoxicity, favorable predicted protein–ligand interactions, acceptable pharmacokinetic properties, and multitarget network pharmacology analyses. These findings provide a preliminary foundation for further optimization and in vivo validation toward the development of novel anticancer therapeutics targeting inflammation-driven and androgen-dependent cancers.