Chin Med J (Engl). 2026 May 19. doi: 10.1097/CM9.0000000000004098. Online ahead of print.

ABSTRACT

High-salt diet (HSD) has emerged as a prevalent environmental factor that exacerbates chronic inflammation and insulin resistance in obesity-associated type 2 diabetes (T2D) by modulating macrophage polarization, metabolic reprogramming, and epigenetic imprinting. Current evidence demonstrates that HSD activates p38/mitogen-activated protein kinase (MAPK), nuclear factor kappa-B (NF-κB), and NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome signaling pathways, by which it drives macrophage polarization toward a proinflammatory M1 phenotype while inducing a glycolysis-dominant metabolic shift, thereby establishing a persistent "metabolic memory". Moreover, HSD orchestrates metabolic memory in macrophages through coordinated epigenetic machinery, including histone modifications (Trimethylation of histone H3 at lysine 4 [H3K4me3] and Acetylation of histone H3 at lysine 27 [H3K27ac]), DNA methylation, and noncoding RNAs (e.g., long non-coding RNA MALAT1 and miR-155), leading to sustained inflammatory phenotypes. In multiple metabolic organs (e.g., adipose tissue, liver, pancreas, and gut), the HSD-macrophage axis aggravates systemic insulin resistance through shared proinflammatory signaling and other tissue-specific mechanisms. Most importantly, therapeutic strategies targeting the NLRP3 inflammasome, metabolic pathways, and epigenetic alterations offer novel approaches for managing metabolic inflammation. Future investigations are encouraged to leverage lineage tracing, single-cell sequencing, and spatial multi-omics technologies to advance the development of precision medicine for macrophage-associated metabolic disorders.

PMID:42156155 | DOI:10.1097/CM9.0000000000004098

Cell Rep Med. 2026 Mar 30:102708. doi: 10.1016/j.xcrm.2026.102708. Online ahead of print.

ABSTRACT

Intratumor heterogeneity (ITH) undermines transcriptome-based stratification in intrahepatic cholangiocarcinoma (iCCA). Here, we integrate multi-omics data from multi-region, single-region, and single-cell RNA sequencing cohorts to systematically characterize gene expression ITH. We uncover that immune and stromal heterogeneity are primary drivers of ITH, leading to misclassification of a median 27.8% of tumors by existing subtyping systems. To overcome this, we identify a low-intratumor-heterogeneity/high-intertumor-variability (LIHV) gene set and develop an ITH-insensitive classification system defining five subgroups: inflammatory (SI), metabolic (SII), atypical (SIII-1), immune-silent (SIII-2), and neurodegenerative (SIII-3). These subgroups exhibit distinct clinical outcomes, molecular features, immune landscapes, and therapeutic vulnerabilities. GPRC5A and VTCN1 serve as robust immunohistochemical biomarkers for SI and SIII tumors, while serum CEA and CA19-9 identify inflammatory iCCA. Therapeutically, HSP90 inhibition synergizes with anti-PD1 in inflammatory iCCA, whereas combined anti-PD1 and anti-TIM3 suppresses neurodegenerative iCCA. Collectively, our study provides a robust molecular framework and actionable therapeutic strategies for iCCA.

PMID:41916296 | DOI:10.1016/j.xcrm.2026.102708

Nat Commun. 2026 Mar 20;17(1):2655. doi: 10.1038/s41467-026-70193-w.

ABSTRACT

Pulmonary fibrosis represents a progressive interstitial lung disease marked by excessive extracellular matrix deposition and architectural distortion. Vascular endothelial cells critically contribute to fibrogenesis through paracrine secretion of pro-fibrotic mediators, yet their mechanobiological regulation remains elusive. Using integrated single-cell multi-omics profiling of human pulmonary fibrosis specimens and experimental fibrosis models induced by bleomycin or silica, we identify mechanosensitive Piezo1 upregulation in Endothelial cells as a hallmark of fibrotic progression. Endothelial-specific Piezo1 knockout significantly attenuates Bleomycin-induced fibrotic remodeling in male mice, establishing its pathogenic necessity. Mechanistically, PIEZO1 activation promotes pulmonary fibrosis development via CAPN2-mediated STAT3 phosphorylation, which may regulate the secretion of the pro-fibrotic molecule interleukin-33. These findings suggest that the endothelial PIEZO1-CAPN2-STAT3-IL33 axis is a potential therapeutic target for PF intervention.

PMID:41862476 | PMC:PMC13004862 | DOI:10.1038/s41467-026-70193-w