A very recent study published in British Journal of Pharmacology by Xin et al. (2025) showed that knocking out ninjurin 1 (NINJ1) reduces acinar cell necrosis and the release of oxidised mitochondrial DNA (ox-mtDNA) from these cells, in cell models of acute and mild acute pancreatitis, and protects against acute pancreatitis in mouse models. Authors used sodium taurocholate (STC) and ceruletide (caerulein, CER) to induce acute pancreatitis (AP) and mild acute pancreatitis (MAP), respectively (Xin et al., 2025). They showed that both sodium taurocholate and ceruletide significantly increase the extracellular ox-mtDNA levels (ox-mtDNA released from acinar cells) and necrosis of acinar cells. In contrast, knocking out NINJ1 in these cells was shown to markedly decrease both necrosis and the release of ox-mtDNA, following treatment of cells with sodium taurocholate or ceruletide, pointing to the involvement of NINJ1 in both acinar cell necrosis and the release of ox-mtDNA from acinar cells, in cell models of both acute pancreatitis and mild acute pancreatitis (Xin et al., 2025). However, knocking out NINJ1 did not completely reverse these events (i.e. sodium taurocholate- or ceruletide-induced acinar cell necrosis and the release of ox-mtDNA to the extracellular space), suggesting that another player, similar to NINJ1, might exist (Xin et al., 2025). Authors also reported that the inhibition of ferroptosis, pyroptosis, apoptosis and necroptosis of pancreatic acinar cells alone was insufficient to completely block sodium taurocholate-induced acinar cell death (necrosis). This suggests that sodium taurocholate-induced acinar cell death is not attributable to a single regulated cell death mechanism (Xin et al., 2025). NINJ1, a transmembrane (TM) protein, mediates plasma membrane permeabilization and rupture during the final lytic phase of multiple regulated cell death mechanisms such as pyroptosis, ferroptosis, parthanatos, H2O2-induced necrosis, secondary necrosis and cuproptosis (Dondelinger et al., 2023; Kayagaki et al., 2021). However, NINJ1 does not contribute to plasma membrane rupture during necroptosis; and therefore, it dispensable for plasma membrane rupture during necroptosis (Dondelinger et al., 2023; Kayagaki et al., 2021). Another very recent study published this year reported that another protein, sialic acid-binding Ig-like lectin 12 (SIGLEC12), mediates plasma membrane rupture during necroptotic cell death (Noh et al., 2025). Authors identified SIGLEC12 as a main mediator of necroptosis downstream of MLKL at the plasma membrane rupture step, and showed that cells without SIGLEC12 are defective in necroptosis-induced plasma membrane rupture (Noh et al., 2025). Besides, they found a high amino acid similarity between SIGLEC12 and NINJ1, pointing to possible functional homology (Noh et al., 2025). Since Xin et al. (2025) observed that the deletion of NINJ1 does not completely reverse sodium taurocholate- or ceruletide-induced acinar cell death and the release of ox-mtDNA to the extracellular space, and that the inhibition of different regulated cell death mechanisms alone could not completely block sodium taurocholate-induced acinar cell death, we hypothesised that, in addition to NINJ1, SIGLEC12, another recently identified membrane-rupturing protein, might be involved in acinar cell necrosis and the release of ox-mtDNA following the treatment of cells with sodium taurocholate and ceruletide (i.e. in cell models of acute pancreatitis and mild acute pancreatitis). The inhibition of necroptosis by necrostatin-1 decreases cell death in sodium taurocholate-induced pancreatic acinar cells, but only to certain extent (Ouyang et al., 2021; Xin et al., 2025), showing that necroptosis, in addition to other regulated cell death programs, are involved in sodium taurocholate-induced acinar cell death. Since SIGLEC12 mediates plasma membrane rupture and lytic cell death during necroptosis (Noh et al., 2025), similar to NINJ1 in most other cell death programs (Dondelinger et al., 2023; Kayagaki et al., 2021), SIGLEC12 might also contribute to plasma membrane permeabilization and rupture in acinar cells following the induction with sodium taurocholate, promoting acinar cell lytic death and the release of ox-mtDNA from acinar cells to the extracellular space. This explains why the deletion of NINJ1 fails to completely reverse sodium taurocholate- or ceruletide-induced acinar cell death and the release of ox-mtDNA (Xin et al., 2025). In other words, both of these membrane-rupturing proteins might contribute to acinar cell plasma membrane rupture in response to sodium taurocholate, suggesting that both NINJ1 and SIGLEC12 might be involved in pancreatitis (both acute and mild acute forms). To test these hypotheses, further research is needed where SIGLEC12 knockout (SIGLEC12-KO) pancreatic acinar cells are treated with sodium taurocholate- or ceruletide, and subsequently the levels of cell death (necrosis) and the release of ox-mtDNA are quantified in these cells. Besides, NINJ1 and SIGLEC12 double knockout (DKO) acinar cells should be used in comparison with NINJ1 single knockout and SIGLEC12 single knockout acinar cells in order to determine the relative importance of these two proteins in acute and mild acute pancreatitis. Since sodium taurocholate induces multiple forms of regulated cell death (including ferroptosis, pyroptosis, apoptosis and necroptosis) in acinar cells in cell models of acute pancreatitis, NINJ1 might particularly mediate plasma membrane rupture if ferroptotic, pyroptotic and apoptotic events are more dominant. However, SIGLEC12 might mediate plasma membrane rupture if necroptotic events are more common. Hypothetically, combined inhibition of both NINJ1 and SIGLEC12 at the clinic might significantly protect against acinar cell plasma membrane rupture and lytic cell death in the treatment of pancreatitis, compared to the inhibition of either protein alone. By targeting the oligomerization of both proteins, plasma membrane rupture events in acinar cells can be markedly limited (if not fully) in the context of pancreatitis. For instance, the inhibition of plasma membrane rupture with NINJ1 antibodies has been previously found to limit tissue injury in different disease models such as liver ischaemia–reperfusion injury model (Kayagaki et al., 2023). Similarly, combined targeted treatment with both NINJ1 and SIGLEC12 antibodies or with small molecules targeting these proteins might potentially benefit patients with (acute/mild acute) pancreatitis at the clinic. However, further in vivo studies are required to test this hypothesis before future clinical research. Caglar Berkel: Conceptualization; writing—original draft; writing—review and editing. The author declares no conflict of interest.
Çağlar Berkel (Sun,) studied this question.