A Novel Compound ZYZ329 Suppresses Non-Small Cell Lung Cancer Via Microbiome-Derived Indole-3-Lactic Acid-PIGL Signalling

Background and purpose: Gut microbiota-derived metabolites may influence NSCLC progression, but pharmacologically tractable gut-lung mechanisms remain unclear. We examined whether ZYZ329 suppresses NSCLC through microbiota-dependent metabolic remodelling and downstream tumour signalling. Experimental Approach: Antitumour activity of oral ZYZ329 was evaluated in A549 xenografts, including antibiotic-treated pseudo-germ-free mice. Faecal 16S rRNA sequencing, serum metabolomics, in vitro caecal incubation, bacterial culture/co-culture, tumour transcriptomics, and molecular and cellular assays were used to identify microbiota-metabolite changes and downstream mechanisms. Key results: ZYZ329 inhibited xenograft growth in vivo despite weak direct cytotoxicity in NSCLC cells, and this effect was lost in pseudo-germ-free mice. 16S rRNA sequencing showed enrichment of Lactobacillus and reduction of the Escherichia-Shigella genus, while metabolomics identified increased circulating indole-3-lactic acid (ILA). ZYZ329 increased ILA production in caecal contents. In bacterial culture experiments, ZYZ329 restrained Escherichia coli growth, reduced indole accumulation and favoured Lactobacillus johnsonii-dependent ILA generation in co-culture. PIGL was down-regulated in tumours, ILA reduced STAT3 Tyr705 phosphorylation and suppressed PIGL expression, and PIGL knockdown impaired malignant phenotypes. Conclusions and implications: ZYZ329 exerts microbiota-dependent antitumour activity in NSCLC, associated with increased microbial ILA and suppression of the STAT3-PIGL axis. These findings support gut microbial metabolism as a therapeutically relevant target in NSCLC.