Liao Zhi-Qiang, Yang Jing, Yang Zhou-Sheng, Wei Zu-Xing, Qi Xiao-Yan, Yang Le-Ping, Yao Hong-Liang, Guo Zhu-Shu
Department of General Surgery, The Second Xiangya Hospital of Central South University, Changsha 410011, China.
Department of Wound Care Clinic, The Second Xiangya Hospital of Central South University, Changsha 410011, China.
Int Immunopharmacol. 2025 Sep 23;162:115171. doi: 10.1016/j.intimp.2025.115171. Epub 2025 Jul 4.
During severe acute pancreatitis (SAP), the circulating free fatty acid levels are elevated, and this elevation correlates with a poor prognosis. However, the precise mechanisms by which lipid metabolism influences the progression of SAP remain unclear. Considering that stearoyl-CoA desaturase (SCD1) is a key lipid-modifying enzyme, we investigated its role in SAP. Using caerulein and ligation-induced SAP models along with RNA sequencing, we found that SCD1 is upregulated in SAP models. Through studies with Scd1 knockout mice and acinar cells, we determined that the absence of SCD1 exacerbates pathological damage and inflammatory responses in SAP model mice while inducing lipid peroxidation and ferroptosis. By employing Sirt mice and a lipid metabolomic analysis, we found that SIRT1 upregulates SCD1 expression through deacetylation, thereby contributing to ferroptosis resistance by altering the fatty acid composition. By examining the effects of monounsaturated fatty acids (palmitoleic acid) on SCD1 siRNA-transfected cells, we observed that MUFAs can counteract lipid peroxidation and promote SIRT1 expression, forming a positive feedback loop that resists ferroptosis in SAP model mice. Our findings indicate that SCD1-mediated cellular lipid and redox homeostasis plays a key role in SAP defense, suggesting a potential mechanism for SAP prevention and treatment.
在重症急性胰腺炎（SAP）期间，循环游离脂肪酸水平升高，且这种升高与预后不良相关。然而，脂质代谢影响SAP进展的精确机制仍不清楚。鉴于硬脂酰辅酶A去饱和酶（SCD1）是一种关键的脂质修饰酶，我们研究了其在SAP中的作用。使用雨蛙肽和结扎诱导的SAP模型以及RNA测序，我们发现SCD1在SAP模型中上调。通过对Scd1基因敲除小鼠和腺泡细胞的研究，我们确定SCD1的缺失会加剧SAP模型小鼠的病理损伤和炎症反应，同时诱导脂质过氧化和铁死亡。通过使用Sirt小鼠和脂质代谢组学分析，我们发现SIRT1通过去乙酰化上调SCD1表达，从而通过改变脂肪酸组成促进铁死亡抗性。通过检测单不饱和脂肪酸（棕榈油酸）对SCD1 siRNA转染细胞的影响，我们观察到单不饱和脂肪酸可以抵消脂质过氧化并促进SIRT1表达，形成一个正反馈回路，抵抗SAP模型小鼠中的铁死亡。我们的研究结果表明，SCD1介导的细胞脂质和氧化还原稳态在SAP防御中起关键作用，为SAP的预防和治疗提供了一种潜在机制。
