Figure 7.

iHPCAL1 protects against ferroptosis-associated acute pancreatitis in mice. (a) Representative images of pancreatic histology in cerulein-induced pancreatitis in Gpx4 wild-type (WT) and KO mice with or without iHPCAL1 treatment (10 mg/kg; bar = 200 µm). Histological scores for acinar cell death, leukocyte infiltration, and edema at 12 h after the last cerulein treatment were evaluated. Data are presented as mean ± SD; n = 6 mice/group; one-way ANOVA test on all pairwise combinations. (b-m) In parallel, serum AMY (b), pancreatic trypsin activity (c), pancreatic MPO activity (d), serum LDH (e), serum HMGB1 (f), serum TNF (g), serum IL6 (h), serum IL1B (I), pancreatic Ptgs2 mRNA (j), pancreatic MDA (k), pancreatic CASP3 activity (l), and pancreatic HPCAL1 protein (m) were assayed at 12 h after the last cerulein treatment. Data are presented as mean ± SD; n = 6 mice/group; one-way ANOVA test on all pairwise combinations. (n) Schematic depicting the role of HPCAL1 in the promotion of ferroptosis by mediating the autophagic degradation of CDH2. Ferroptosis activators (e.g., erastin and RSL3), but not apoptosis inducers (e.g., STS) or classic autophagy inducers (e.g., HBSS and rapamycin) induce PRKCQ phosphorylation on T538, which leads to HPCAL1 phosphorylation on T149. Phosphorylated HPCAL1 acts as a selective autophagy receptor for CDH2 and mediates the degradation of CDH2 in lysosomes. The loss of CDH2 decreases mechanotransduction and ultimately reduces cell connections, thereby accelerating the lipid peroxidation of ferroptosis.