SHP2 inhibitor PHPS1 regulates macrophage-adipocyte interaction to alleviate inflammation and adipocyte insulin resistance, via NF-κB suppression and IRS-1/GLUT-4 restoration

This study explored the anti-inflammatory and insulin resistance-regulating effects of SHP2 inhibitor PHPS1 using a Transwell co-culture system of adipocytes and macrophages to mimic the in vivo adipose microenvironment. Two models were established: TNF-α-stimulated 3T3-L1 adipocytes (single culture) and LPS-induced insulin-resistant 3T3-L1/RAW 264.7 co-cultures. After 24 h of 10 μM PHPS1 pretreatment, ELISA, qRT-PCR, and Western blotting were used to detect inflammatory factors, gene expression, and protein phosphorylation, respectively. In TNF-α-stimulated adipocytes, PHPS1 reduced pro-inflammatory factors (IL-6: 62.35%, IL-1β: 54.10%, MCP-1: 49.19%), increased IL-10 (103.98%), and downregulated iNOS/COX-2 mRNA. In LPS-induced co-cultures, PHPS1 decreased IL-6 (68.73%), IL-1β (63.01%), MCP-1 (47.79%), upregulated IL-10 (167.49%), and inhibited iNOS/COX-2 mRNA. Mechanistically, PHPS1 suppressed NF-κB pathway phosphorylation (pp65, pIkkα) in both models, reversed LPS-induced pIRS-1 Ser307 phosphorylation (61.12% reduction), and upregulated GLUT-4 (198.0%). Thus, PHPS1 alleviates inflammation via NF-κB inhibition and improves insulin resistance by restoring the IRS-1/GLUT-4 axis, making it a potential candidate for insulin resistance-related metabolic diseases.