The landscape of clinical management for metastatic melanoma (MM) and other solid tumors has been modernized by the advent of immune checkpoint inhibitors (ICI), including programmed cell death-1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors. While these agents demonstrate efficacy in suppressing tumor growth, they also lead to immune-related adverse events (irAEs), resulting in the exacerbation of autoimmune diseases such as rheumatoid arthritis (RA), ulcerative colitis (UC), and Crohn’s disease (CD). The immune checkpoint inhibitors offer promising advancements in the treatment of melanoma and other cancers, but they also present significant challenges related to irAEs and autoimmune diseases. Ongoing research is crucial to better understand these challenges and develop strategies for mitigating adverse effects while maximizing therapeutic benefits. In this manuscript, we addressed this challenge using network-based approaches by constructing and analyzing the molecular and signaling networks associated with tumor-immune crosstalk. Our analysis revealed that IL6 is the key regulator responsible for irAEs during ICI therapies. Furthermore, we conducted an integrative network and molecular-level analysis, including virtual screening, of drug libraries, such as the Collection of Open Natural Products (COCONUT) and the Zinc15 FDA-approved library, to identify potential IL6 inhibitors. Subsequently, the compound amprenavir was identified as the best molecule that may disrupt essential interactions between IL6 and IL6R, which are responsible for initiating the signaling cascades underlying irAEs in ICI therapies.

The landscape of clinical management for metastatic melanoma (MM) and other solid tumors has been modernized by the advent of immune checkpoint inhibitors (ICI), including programmed cell death-1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors. While these agents demonstrate efficacy in suppressing tumor growth, they also lead to immune-related adverse events (irAEs), resulting in exacerbation of autoimmune diseases such as Rheumatoid arthritis (RA), Ulcerative colitis (UC), and Crohn’s disease (CD). The immune checkpoint inhibitors offer promising advancements in the treatment of melanoma and other cancers, but they also present significant challenges related to irAEs and autoimmune diseases. Ongoing research is crucial to better understand these challenges and develop strategies for mitigating adverse effects while maximizing therapeutic benefits. In this manuscript, we addressed this challenge using network-based approaches by constructing and analyzing molecular and signaling networks associated with tumor-immune cross-talk.. Our analysis revealed that IL6 is the key regulator responsible for irAEs during ICI therapies. Furthermore, we conducted an integrative network and molecular-level analysis, including virtual screening, of drug libraries, such as the Collection of Open Natural Products (COCONUT) and the Zinc15 FDA-approved library, to identify potential IL-6 inhibitors.. Subsequently, the compound amprenavir was identified as the best molecule that may disrupt essential interactions between IL6 and IL6R responsible for initiating signaling cascades underlying irAEs in ICI therapies.

Objective: Lung cancer remains the leading cause of cancer-related mortality worldwide, with significant resistance to conventional therapies, highlighting the urgent need for novel therapeutic strategies. Moringa oleifera (M. oleifera), a medicinal plant rich in diverse bioactive compounds, has shown promising potential for anti-lung carcinoma activity. This study investigates the molecular mechanisms underlying the therapeutic effects of M. oleifera bioactive compounds through an integrated systems biology and molecular docking approach. By constructing comprehensive compound-target-pathway networks, we aim to elucidate the multitarget pharmacology of M. oleifera compounds, providing valuable insights into their potential as therapeutic candidates. Methods: Bioinformatics tools were used to identify 180 phytochemicals from M. oleifera, filtered using Lipinski’s Rule of Five and ADMET properties, yielding 14 lead compounds. Protein-protein interaction (PPI) analysis identified 89 overlapping lung cancer targets, with EGFR being the most enriched in pathway enrichment analysis. Results: In the analysis, Caffeic acid showed the highest binding affinity (-28.97 kcal/mol) with EGFR through molecular docking and maintained stability during molecular dynamics simulations. This interaction also modulates 12 pathways critical to lung cancer, including MAPK, JAK-STAT, and PI3K/AKT pathways. The overall result suggests that Caffeic acid is an EGFR-mediated oncogenic signalling inhibitor. Conclusion: Caffeic acid is a potential candidate for lung cancer therapy, warranting further experimental validation to translate these findings into clinical applications.

Lung cancer remains the leading cause of cancer-related mortality worldwide, with significant resistance to conventional therapies, highlighting the urgent need for novel therapeutic strategies. Moringa oleifera (M. oleifera), a medicinal plant rich in diverse bioactive compounds, has shown promising potential for anti-lung carcinoma activity. This study investigates the molecular mechanisms underlying the therapeutic effects of M. oleifera bioactive compounds for their anti-lung cancer activities through an integrated network modeling and molecular docking approach. By constructing comprehensive compound–target–lung cancer pathway networks, we aim to elucidate the multitarget pharmacology of M. oleifera compounds, providing valuable insights into their potential as therapeutic candidates. Computational pipeline was applied to identify 180 phytochemicals from M. oleifera, filtered using Lipinski’s Rule of Five and ADMET properties, resulting in 10 lead compounds followed by their potential biological target proteins in regulating lung cancer progression. We identified 80 targeted proteins involved in lung cancer, with EGFR being the most enriched in pathway enrichment analysis. In the molecular docking analysis, caffeic acid showed the highest binding score (−28.97 kcal/mol) with EGFR forming stable complex during molecular dynamics simulations compared to the known EGFR inhibitor ‘erlotinib’. The overall results suggest that caffeic acid, a key bioactive compound in M. oleifera, is an EGFR-mediated oncogenic signaling inhibitor for lung cancer therapy, warranting further experimental validation to translate these findings into clinical applications.