SIK1 promotes ferroptosis resistance in pancreatic cancer via HDAC5-STAT6-SLC7A11 axis.

The activation of protein kinases is ubiquitous in pancreatic ductal adenocarcinoma (PDAC), yet its impact on ferroptosis remains unclear. SIK1 was identified as a key regulator of ferroptosis resistance in PDAC by kinase database screening. Targeting SIK1 could significantly reverse ferroptosis resistance and enhance cytotoxic effects of gemcitabine via increasing ferroptosis sensitivity in PDAC cells. Mechanistically, SIK1 phosphorylated HDAC5 at Ser498 residue and promoted its interaction with 14-3-3 protein, which further protected HDAC5 from TRIM28-mediated ubiquitylation and degradation. SIK1-stabilized HDAC5 deacetylated STAT6 and enhanced its transcriptional activity to upregulate SLC7A11 expression, ultimately rendering PDAC cells resistance to ferroptosis. SIK1 inhibitor (YKL-05-099) could synergistically enhance the antitumor effects of gemcitabine in organoid and patient-derived xenograft (PDX) models by inducing ferroptosis, suggesting a novel therapeutic target for PDAC. Clinically, SIK1 was positively correlated with SLC7A11 expression in PDAC specimens, which was associated with poor prognosis. These findings unveil a crucial mechanism through which PDAC counters ferroptosis via SIK1-mediated HDAC5 stabilization and subsequent SLC7A11 upregulation. This study underscores the promising potential of targeting SIK1-HDAC5 axis as a therapeutic strategy to overcome drug resistance in PDAC.