Abstract Calcium oxalate nephrolithiasis is commonly viewed as a consequence of urinary supersaturation, although crystal retention and renal injury are also influenced by gut microbiota dysbiosis and local tissue environment. In a recent study by Li et al , published in The Journal of Pathology , the authors integrated human metagenomic and metabolomic analyses with mouse and tubular cell models to identify indole‐3‐propionic acid (IPA) as a key gut‐derived metabolite associated with kidney stone disease. Patients with calcium oxalate stones showed altered gut microbial composition and reduced serum IPA levels, which were inversely related to stone burden. In experimental models, IPA supplementation reduced renal crystal deposition, preserved kidney function, and limited tubular injury and apoptosis. Mechanistic studies showed that IPA activated aryl hydrocarbon receptor (AhR) in tubular epithelial cells, increased suppressor of cytokine signaling 3 (SOCS3) expression, and suppressed signal transducer and activator of transcription 1 (STAT1) phosphorylation and nuclear accumulation. These findings were supported by complementary activation, inhibition, knockdown, and overexpression experiments. Collectively, the data suggest that IPA protects renal epithelial cells through the AhR–SOCS3–STAT1 signaling pathway and may offer a potential therapeutic approach for calcium oxalate nephropathy. © 2026 The Pathological Society of Great Britain and Ireland.
Abstract Calcium oxalate (CaOx) nephropathy is a highly prevalent urological disease worldwide. Gut microbiota dysbiosis and host metabolic dysregulation are recognized as pivotal drivers in disease pathogenesis, yet the underlying mechanisms remain incompletely understood. In this study, by integrating metagenomics and metabolomics, we identified dysregulation of tryptophan metabolites in patients with CaOx nephrolithiasis, with microbiota‐derived indole‐3‐propionic acid (IPA) as the most discriminatory differential metabolite. Oral IPA supplementation markedly reduced renal CaOx crystal deposition and tubular injury in a CaOx nephropathy murine model. Mechanistically, IPA activated the aryl hydrocarbon receptor (AhR), which translocated to the nucleus and transcriptionally upregulated suppressor of cytokine signaling 3 (SOCS3)—a negative regulator of signal transducer and activator of transcription 1 (STAT1)—thereby suppressing STAT1 phosphorylation, alleviating oxalate‐induced tubular cell injury and apoptosis, and inhibiting CaOx crystal deposition. Our findings identify tryptophan metabolite alteration as a critical metabolic signature of CaOx nephropathy and demonstrate that microbiota‐derived IPA attenuates oxalate‐induced renal tubular cell injury and apoptosis via the AhR–SOCS3–STAT1 axis. © 2026 The Pathological Society of Great Britain and Ireland.
Abstract Propionic acidemia (PA) is a neurometabolic disorder caused by propionyl‐CoA carboxylase deficiency with frequent neurological involvement, yet cell‐type‐specific mechanisms remain poorly defined. We established human induced pluripotent stem cell (iPSC)‐derived astrocytes (iAs) from patients harboring PCCA or PCCB mutations and investigated functional and molecular alterations associated with PA. Both control‐ and patient‐derived iPSCs yielded astrocyte‐enriched cultures through a neural progenitor intermediate, with expression of astrocyte‐associated markers. Patient iAs showed impaired mitochondrial respiration (lower basal and maximal oxygen consumption and ATP‐linked respiration), together with reduced high‐affinity uptake of glutamate and glycine neurotransmitters and evidence of disturbed Ca 2+ homeostasis. They also migrated faster in wound‐healing assays and displayed reactive‐like features, including increased GFAP and connexin 43 (Cx43) protein levels and elevated AQP4 mRNA levels. Targeted miRNA profiling revealed upregulation of miR‐124‐3p, miR‐9‐5p, and miR‐125b‐5p, concomitant with downregulation of miR‐146a‐5p, miR‐155‐5p, and miR‐145‐5p. Consistent with these changes, reported target genes associated with innate immune signaling ( IRAK1 , TRAF6 , TAB2 ), astrocyte remodeling ( GFAP ), and water/ion homeostasis ( AQP4 ) were upregulated. Inflammatory and proliferative markers were likewise increased, including IL1B , TNF , and MKI67 . Together, these convergent alterations suggest a phenotype characterized by impaired homeostatic functions and reactive‐like features, which may heighten neural network vulnerability under metabolic stress. Collectively, our data support astrocyte dysfunction as a potential contributor to PA neuropathology and highlight patient‐derived iAs as a useful model for future mechanistic studies and therapeutic exploration. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Germline variations contribute to esophageal squamous cell carcinoma (ESCC) susceptibility. We identified a germline deletion (exons 7-8) in HIF3A in an ESCC family and investigated its functional impact using CRISPR/Cas9-engineered cells and Hif3a-eKO1 mice (heterozygous for exons 7-8 deletion). Multi-omics analysis of Hif3a-eKO1 and WT mice revealed dysregulated pathways in normal esophagus and during 4NQO-induced carcinogenesis, with key biomarkers validated by immunohistochemistry. Hif3a deficiency enhanced ESCC cell proliferation and invasion in vitro and accelerated 4NQO-induced tumorigenesis in vivo, with Hif3a-eKO1 mice developing more and larger neoplastic lesions. Multi-omics analysis revealed downregulation of cytokeratin-related genes (notably Krt17) and γδ T cells in normal esophagus of Hif3a-eKO1 compared with WT. Consistently reduced Krt17 expression in Hif3a-eKO1 was confirmed by both esophageal immunohistochemistry and cellular Western blot analyses. During 4NQO-induced carcinogenesis, Hif3a deficiency upregulated DNA damage response markers, including Krüppel-like factor 4 (Klf4) and ATR serine/threonine kinase (Atr). Notably, epithelial cells with abundant γH2AX foci lacked Krt17 expression, while Krt17-positive cells showed minimal γH2AX foci. Heterozygous germline Hif3a deletion (exons 7-8) may promote ESCC by disrupting esophageal barrier function-impairing Krt17-mediated epithelial integrity and reducing γδ T cells-while exacerbating genomic instability. These findings reveal ESCC predisposition mechanisms and therapeutic targets. © 2026 The Pathological Society of Great Britain and Ireland.
Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor originating from calcitonin producing C-cells and accounts for 1-5% of thyroid cancers. Total thyroidectomy is curative in localized disease (N0), whereas lymph node metastases (N1) are associated with poorer prognosis. However, the molecular mechanisms driving the metastatic shift remain poorly understood. This study aimed to identify miRNA features linked to metastatic spread in MTC, focusing on the transition from N0 to N1. Co-expression networks were constructed for N0 and N1 tumors, and differential connectivity analysis was used to identify key miRNAs acting as regulatory hubs. Functional annotation of their target genes was performed using the Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and Reactome pathway analyses. Validation experiments were carried out in MTC cells to evaluate the effects of selected miRNAs on cell proliferation, survival, and MAPK pathway activation. Network analysis revealed distinct miRNA co-expression patterns between N0 and N1 tumors. Differential network analysis highlighted miR-145-3p as a central regulatory hub, exhibiting 29 altered co-expression changes and a marked loss of connectivity in N1. Target enrichment identified 59 validated genes, including key oncogenic drivers such as MYC, PTEN, BCL2, PIK3CA, AKT1, and MAPK7. In MTC cells, simultaneous inhibition of miR-145-3p together with its top co-expressed miRNAs increased proliferation and survival, and enhanced ERK phosphorylation, indicating MAPK pathway activation and a shift toward a more aggressive phenotype. In conclusion, this study identifies a miRNA regulatory hub centered on miR-145-3p that is associated with metastatic progression and highlights the value of network-based approaches in uncovering mechanisms of cancer dissemination. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
