J Inflamm Res. 2026 Sep 22;19:606503. doi: 10.2147/JIR.S606503. eCollection 2026.

ABSTRACT

BACKGROUND: Neutrophil extracellular traps (NETs) were key factors mediating inflammatory injury in acute pancreatitis (AP). To this end, there was an urgent need to identify precise and effective therapeutic targets that modulate NETs formation, providing new ideas for the prevention and treatment of AP pancreatitis injury.

GAP: To address this gap, we investigated the potential involvement of the myo-inositol metabolism in modulating NETs and inflammatory damage during AP.

METHODS: Multi-omics analysis identified myo-inositol metabolism as critical. We then established the in vitro NETs model using phorbol-12-myristate-13-acetate (PMA) to investigate the role and regulatory mechanism of inositol-3-phosphate synthase 1 (ISYNA1) on NETs formation. Finally, the findings were validated in the classic AP mouse model to verify the correlation between myo-inositol metabolism and AP pathogenesis.

RESULTS: Multiple omics analyses showed that the myo-inositol metabolic pathway is the most significant, and the key enzyme ISYNA1 involved in myo-inositol synthesis was significantly reduced. ISYNA1 was significantly downregulated in both the in vitro NETs model and in neutrophils infiltrating the pancreatic tissue of AP mice. Meanwhile, exogenous supplementation of ISYNA1 or myo-inositol significantly inhibited the NETs formation in vitro and inflammatory injury in AP mice. Mechanistically, downregulation of ISYNA1 led to reduced myo-inositol synthesis, thereby promoting NETs formation via modulation of the PI3K/AKT pathway.

CONCLUSION: ISYNA1 and myo-inositol metabolism were among the key links that regulated NETs formation and inflammatory injury in AP. Therefore, enhancing ISYNA1 and myo-inositol metabolism might serve as a potential intervention target for treating acute organ injury in AP.

PMID:42801157 | PMC:PMC13615823 | DOI:10.2147/JIR.S606503

JHEP Rep. 2026 Feb 18;8(5):101790. doi: 10.1016/j.jhepr.2026.101790. Online ahead of print.

ABSTRACT

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) exhibits diverse aetiologies and molecular heterogeneity, with a median 5-year overall survival of <70% due to high recurrence rates following curative-intent surgery. This study investigated the complex tumour microenvironment (TME) in HCC and explored interactions between various cell types and their roles in disease recurrence.

METHODS: Using a multi-omics approach on multi-region samples of surgically resected HCC from the PLANet 1.0 cohort (NCT03267641), we performed spatial transcriptomics on 17 tissue samples from four patients and bulk RNA sequencing on 329 sectors from 90 patients. Findings were validated using immunofluorescence and multiplex immunohistochemistry.

RESULTS: Our analysis revealed extensive intra- and intertumour gene expression heterogeneity and identified a specific subset of endothelial cells (ECs), INTS6⁺ ECs, enriched and spatially colocalised with tumour cells in primary tumours from patients with recurrence (p = 0.021, n = 49). A significant ANGPTL4-SDC1 ligand-receptor interaction was identified between INTS6⁺ ECs and tumour cells. Notably, INTS6⁺ ECs were enriched in microvascular invasion regions and spatially colocalised with tumour cells in patients with recurrence (p = 0.036, n = 53). These findings highlight endothelial-tumour cell interactions within the TME as potential therapeutic targets.

CONCLUSIONS: INTS6⁺ ECs are enriched in microvascular invasion regions and spatially colocalised with tumour cells in recurrent HCC, suggesting a potential role in disease recurrence and representing a promising therapeutic target within the TME.

IMPACT AND IMPLICATIONS: The spatial co-localisation of cell types plays a significant role in the recurrence of hepatocellular carcinoma. In this study, we have pinpointed a particular group of endothelial cells, known as INTS6+ endothelial cells, which are spatially colocalised with tumour cells and enriched in microvascular invasion regions in patients experiencing recurrence. These discoveries highlight novel therapeutic targets that focus on endothelial cell interactions within the tumour microenvironment to prevent recurrence and enhance overall patient survival.

PMID:41950768 | DOI:10.1016/j.jhepr.2026.101790

JHEP Rep. 2026 Feb 18;8(5):101790. doi: 10.1016/j.jhepr.2026.101790. Online ahead of print.

ABSTRACT

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) exhibits diverse aetiologies and molecular heterogeneity, with a median 5-year overall survival of <70% due to high recurrence rates following curative-intent surgery. This study investigated the complex tumour microenvironment (TME) in HCC and explored interactions between various cell types and their roles in disease recurrence.

METHODS: Using a multi-omics approach on multi-region samples of surgically resected HCC from the PLANet 1.0 cohort (NCT03267641), we performed spatial transcriptomics on 17 tissue samples from four patients and bulk RNA sequencing on 329 sectors from 90 patients. Findings were validated using immunofluorescence and multiplex immunohistochemistry.

RESULTS: Our analysis revealed extensive intra- and intertumour gene expression heterogeneity and identified a specific subset of endothelial cells (ECs), INTS6⁺ ECs, enriched and spatially colocalised with tumour cells in primary tumours from patients with recurrence (p = 0.021, n = 49). A significant ANGPTL4-SDC1 ligand-receptor interaction was identified between INTS6⁺ ECs and tumour cells. Notably, INTS6⁺ ECs were enriched in microvascular invasion regions and spatially colocalised with tumour cells in patients with recurrence (p = 0.036, n = 53). These findings highlight endothelial-tumour cell interactions within the TME as potential therapeutic targets.

CONCLUSIONS: INTS6⁺ ECs are enriched in microvascular invasion regions and spatially colocalised with tumour cells in recurrent HCC, suggesting a potential role in disease recurrence and representing a promising therapeutic target within the TME.

IMPACT AND IMPLICATIONS: The spatial co-localisation of cell types plays a significant role in the recurrence of hepatocellular carcinoma. In this study, we have pinpointed a particular group of endothelial cells, known as INTS6+ endothelial cells, which are spatially colocalised with tumour cells and enriched in microvascular invasion regions in patients experiencing recurrence. These discoveries highlight novel therapeutic targets that focus on endothelial cell interactions within the tumour microenvironment to prevent recurrence and enhance overall patient survival.

PMID:41950768 | DOI:10.1016/j.jhepr.2026.101790