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

Abstract

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 IC50 values of 0.04 µM in both A549 and LNCaP cells, outperforming doxorubicin, while atisine showed moderate activity (IC50: 2.1-2.3 µM). Linoleic acid displayed weak anticancer activity (IC50 >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.

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