Lian Zheng, Du Wei-Hong, Tusup-Han Paizi-Guli, Zhang Yu-Xiang
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
Department of Human Anatomy and Histoembryology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
J Transl Med. 2025 Jun 22;23(1):694. doi: 10.1186/s12967-025-06666-1.
Chronic pancreatitis (CP) is characterized by progressive fibrosis and the activation of pancreatic stellate cells (PSCs). As major producers of collagen-I and fibronectin, PSCs play important roles in pancreatic fibrosis, but few studies have explored methods to target activated PSCs. Notch3, a receptor in the Notch signaling pathway, is highly expressed in activated PSCs, but its specific effect on PSC activation needs to be confirmed. All-trans retinoic acid (ATRA) and the vitamin D analog calcipotriol were able to influence the activation of PSCs, but the relationship between ATRA, calcipotriol and Notch3 has not yet been clarified, and the effects of ATRA and calcipotriol on PSC activation need to be further enhanced.
The impact of Notch3 on pancreatic stellate cell (PSC) activation was evaluated by knocking down Notch3 in PSCs. PSCs were incubated with ATRA and calcipotriol individually or in combination to explore their effects on PSC activation. Notch3-knockdown PSCs were treated with ATRA or calcipotriol under various conditions in vitro to assess their effects on activation. Nuclear receptor inhibition was used to dissect the interplay between Notch3 signaling and ATRA/calcipotriol pathways. The roles of Notch3, ATRA, and calcipotriol were investigated in vivo using a chronic pancreatitis model. Different combinations of these interventions were tested in the chronic pancreatitis model to evaluate their in vivo efficacy.
In this study, we confirmed the important role of Notch3 in PSC activation and found that ATRA and calcipotriol could regulate Notch3 expression. Furthermore, that ATRA and calcipotriol can synergistically prevent and reverse PSC activation, whereas knockdown of Notch3 can enhanced this synergistic effect. In CP model, we verified the effect of targeting Notch3 in combination with ATRA and calcipotriol. At last, we found that ATRA and calcipotriol do not regulate Notch3 through the nuclear receptors RARβ and VDR, but ATRA and calcipotriol depend on Notch3 to regulate PSC activation.
Notch3 is a target for inhibiting PSC activation, ATRA and calcipotriol regulate Notch3 expression in PSCs, and targeting Notch3 in combination with ATRA and calcipotriol against PSC activation holds promise as a novel therapeutic approach for treating pancreatic fibrosis in CP.
慢性胰腺炎（CP）的特征是进行性纤维化和胰腺星状细胞（PSC）的激活。作为I型胶原蛋白和纤连蛋白的主要产生者，PSC在胰腺纤维化中起重要作用，但很少有研究探索靶向激活的PSC的方法。Notch3是Notch信号通路中的一种受体，在激活的PSC中高度表达，但其对PSC激活的具体作用尚需证实。全反式维甲酸（ATRA）和维生素D类似物骨化三醇能够影响PSC的激活，但ATRA、骨化三醇与Notch3之间的关系尚未阐明，且ATRA和骨化三醇对PSC激活的作用有待进一步增强。
通过在PSC中敲低Notch3来评估Notch3对胰腺星状细胞（PSC）激活的影响。将PSC分别与ATRA和骨化三醇单独或联合孵育，以探讨它们对PSC激活的影响。在体外不同条件下，用ATRA或骨化三醇处理Notch3敲低的PSC，以评估它们对激活的影响。使用核受体抑制来剖析Notch3信号与ATRA/骨化三醇途径之间的相互作用。在体内使用慢性胰腺炎模型研究Notch3、ATRA和骨化三醇的作用。在慢性胰腺炎模型中测试这些干预措施的不同组合，以评估它们的体内疗效。
在本研究中，我们证实了Notch3在PSC激活中的重要作用，并发现ATRA和骨化三醇可以调节Notch3的表达。此外，ATRA和骨化三醇可以协同预防和逆转PSC的激活，而敲低Notch3可以增强这种协同作用。在CP模型中，我们验证了联合靶向Notch3与ATRA和骨化三醇的效果。最后，我们发现ATRA和骨化三醇不是通过核受体RARβ和VDR来调节Notch3的，但ATRA和骨化三醇依赖Notch3来调节PSC的激活。
Notch3是抑制PSC激活的一个靶点，ATRA和骨化三醇调节PSC中Notch3的表达，联合靶向Notch3与ATRA和骨化三醇对抗PSC激活有望成为治疗CP中胰腺纤维化的一种新的治疗方法。
