Metabolic dysfunction-associated steatohepatitis (MASH) is driven by complex intercellular communication and regulated cell death pathways. Mitoxyperilysis

Effective cancer immunotherapy requires enhancing tumor-targeted immune responses while limiting pathological inflammation, highlighting an urgent need for single agents that can achieve this balance. Here, we reported that Betrixaban (BT), an FDA-approved Factor Xa inhibitor, functioned as a dual immunomodulator that enhanced antitumor immune responses and suppressed hyperinflammation. BT enhanced innate tumor sensing and adaptive immune responses, partly via epigenetic modulation. In mouse tumor models, BT treatment inhibited tumor growth, accompanied by increased infiltration of activated CD8 ⁺ T cells. Combining BT with immune checkpoint blockade synergistically enhanced antitumor efficacy. Additionally, BT attenuated pathological inflammation by reducing LPS-induced proinflammatory cytokine production and improving survival in a sepsis model. Mechanistically, BT induced a noncanonical, DNA-independent activation of the cGAS-STING pathway, triggering type I interferon signaling without provoking a full inflammatory cascade. These findings highlighted BT as a strategy to promote antitumor immunity while restraining inflammation, potentially improving cancer immunotherapy with reduced inflammatory toxicity.

Background: Intestinal Th17/Treg immune imbalance contributes to type 2 diabetes mellitus (T2DM), but their key molecular regulators remain unclear. Methods: Single-cell and bulk transcriptomic datasets from control diet- and high-fat diet-fed mice were integrated using differential expression, functional enrichment, co-expression network, cell communication, virtual knockout, and machine-learning analyses. Candidate genes were validated in an independent dataset and in colonic tissues from diabetic KKAy and control C57BL/6J mice, and Th17/Treg populations were assessed by flow cytometry. Results: High-fat diet altered colonic immune composition and pathways related to T-cell differentiation, inflammation, and metabolism. TAZ was the only gene shared between Th17/Treg-associated genes and differentially expressed genes across three datasets, with its differential expression confirmed in an independent dataset. Virtual TAZ knockout perturbed pathways involving tight junctions, T-cell receptor signaling, and cell adhesion. T-cell co-expression modules and machine-learning-selected genes were enriched in TGF-β signaling and Th17/Treg differentiation. Diabetic KKAy mice showed increased colonic TAZ, RORγt, IL-17 A, IL-23, and pro-inflammatory cytokines, together with reduced FOXP3 and TGF-β expression. Flow cytometry further confirmed increased Th17 and reduced Treg cells in KKAy mice. Conclusion: TAZ is a conserved candidate associated with intestinal Th17/Treg imbalance and inflammation in T2DM. Although in silico knockout predicted pathway perturbations, its causal role remains to be experimentally established.