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Serum Metabolomics and Multiomics Validation Reveal Zishangan Granule-Induced P53-Bax/Casp3 Signaling in NSCLC
Muhammad Yousif1,2, Fei Liao1, Haoan Wang1
1Agricultural Animal Diseases and Veterinary Public Health Key Laboratory of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.
Abstract:
Nonsmall cell lung cancer (NSCLC) remains a major cause of cancer mortality, underscoring the need for multitarget therapeutic candidates with defined mechanisms. This study investigated the anti-NSCLC activity of Zishangan Granule (ZSG), a four-herb formulation, using serum metabolomics, network pharmacology, molecular docking, public multiomics datasets, and experimental validation. Ultra-performance liquid chromatography-tandem mass spectrometry identified 15 serum-available constituents. Network analysis revealed 111 shared targets between these constituents and NSCLC-associated genes, with Tp53, Casp3, Bax, Pten, and Parp1 identified as core targets. Salvianolic acid L showed favorable predicted binding to these proteins, while public transcriptomic, proteomic, and immunohistochemical datasets supported their disease relevance. In a subcutaneous Lewis lung carcinoma (LLC) model, ZSG reduced tumor weight by 58.3% and increased tumor-cell apoptosis approximately threefold, accompanied by increased expression of P53, P21, Bax, Casp3, Pten, and Parp1. ZSG also reduced viability and colony formation and induced apoptotic morphology in LLC and A549 cells. These findings support the anti-NSCLC activity of ZSG through P53-associated Bax/Casp3 apoptotic signaling and warrant further preclinical evaluation.
Insights
Zishangan Granule (ZSG) demonstrates significant anti-nonsmall cell lung cancer (NSCLC) effects by targeting key apoptosis-related genes. This traditional Chinese medicine formulation warrants further investigation for NSCLC treatment.
Area of Science:
- Integrative oncology
- Pharmacology
- Computational biology
Background:
- Nonsmall cell lung cancer (NSCLC) is a leading cause of cancer mortality, necessitating novel therapeutic strategies.
- Multitarget agents with clear mechanisms are crucial for effective NSCLC treatment.
Purpose of the Study:
- To investigate the anti-NSCLC activity of Zishangan Granule (ZSG), a four-herb formulation.
- To elucidate the molecular mechanisms underlying ZSG's therapeutic effects in NSCLC.
Main Methods:
- Serum metabolomics and network pharmacology to identify active compounds and targets.
- Molecular docking and analysis of public multiomics datasets (transcriptomic, proteomic, IHC).
- In vivo (Lewis lung carcinoma model) and in vitro (LLC, A549 cells) experimental validation.
Main Results:
- Identified 15 serum-available constituents in ZSG; network analysis revealed 111 shared targets with NSCLC genes, highlighting TP53, CASP3, BAX, PTEN, and PARP1 as core targets.
- ZSG significantly reduced tumor weight (58.3%) and increased apoptosis in a Lewis lung carcinoma model, upregulating P53, P21, BAX, CASP3, PTEN, and PARP1.
- In vitro studies showed ZSG reduced cancer cell viability and colony formation, inducing apoptosis.
Conclusions:
- Zishangan Granule exhibits potent anti-NSCLC activity.
- The mechanism involves the TP53-associated BAX/CASP3 apoptotic signaling pathway.
- ZSG demonstrates potential as a novel therapeutic agent for NSCLC, meriting further preclinical research.
