SOX4 Knockdown Represses Pancreatic Acinar Cells Ferroptosis in Acute Pancreatitis Through Reducing LPCAT3 Expression

Acute pancreatitis (AP) is a severe inflammatory disorder characterized by pancreatic acinar cell injury, with ferroptosis, a form of iron-dependent lipid peroxidation-driven cell death, playing a key role in disease progression. However, the molecular mechanisms of ferroptosis regulation in AP remain unclear. SRY-related HMG-box 4 (SOX4) has been implicated in ferroptosis regulation in other pathological conditions, but its role in AP has not been fully elucidated.

In this study, I used caerulein (Cae)-induced primary mouse pancreatic acinar cells as an AP model in vitro, with ferroptosis inhibitor ferrostatin-1 (Fer-1) treatment to assess ferroptotic involvement. I further manipulated SOX4 expression via shRNA-mediated knockdown, and its downstream effects on ferroptosis-related markers were evaluated by qPCR, WB, and lipid peroxidation assays. I also performed chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays to determine whether SOX4 directly regulates Lysophosphatidylcholine Acyltransferase 3 (LPCAT3), a key enzyme in ferroptosis modulation.

I found that SOX4 expression was upregulated in Cae-induced AP cells, correlating with increased ferroptotic markers, including elevated lipid ROS, MDA, and Fe²⁺ levels, and corresponding expression changes of ferroptosis-related proteins. SOX4 knockdown mitigated ferroptosis and improved cell viability. Further analysis revealed that SOX4 binds to the promoter region of LPCAT3 and enhances its transcription. Overexpression of LPCAT3 partially reversed the protective effects of SOX4 silencing.

This study identifies SOX4 as a key regulator of ferroptosis in AP through transcriptional upregulation of LPCAT3. Targeting the SOX4-LPCAT3 axis may represent an advanced therapeutic strategy for mitigating pancreatic injury in AP.