Tangeretin ameliorates hypertriglyceridemic acute pancreatitis by restoring Th17/Treg balance via ROS-mediated STAT3 signaling.

Objective

The mechanisms underlying the progression of hypertriglyceridemic acute pancreatitis (HTGP), particularly CD4+ T cell-mediated immune dysregulation, remain poorly understood.

Methods

To address this issue, clinical data and peripheral blood samples from patients with acute pancreatitis (AP) were analyzed to evaluate CD4+ T cell subsets and inflammatory markers. Bioinformatics analyses identified key regulatory molecules involved in HTGP progression and were validated using transcriptomic datasets. The underlying mechanisms and therapeutic effects of tangeretin were further investigated in HTGP mice and cultured T cells using histopathological, biochemical, molecular, and flow cytometry analyses.

Results

Higher TG levels were associated with a trend toward reduced CD4+ T cell proportions in patients with AP. Bioinformatics analyses identified STAT3 as a potential candidate regulator associated with HTGP-related inflammatory signaling. Mechanistically, HTGP induced oxidative stress, promoted Th17 differentiation, reduced Treg proportions, and was associated with enhanced STAT3 activation, accompanied by pancreatic injury and secondary splenic damage. Tangeretin markedly alleviated tissue injury, suppressed oxidative stress and inflammatory responses, inhibited p-STAT3 activation, and restored Th17/Treg immune homeostasis.

Conclusion

These findings suggest that oxidative stress and STAT3 activation may contribute to CD4+ T cell immune alterations in HTGP. Tangeretin attenuated oxidative stress and STAT3 activation and was associated with improved immune homeostasis, supporting its potential protective effects against HTGP.