Gangi Alexandra, Li Tony W H, Lim Youngyi, Chandla Swati, Floris Andrea, Khangholi Arash, Tomasi Maria Lauda, Lu Shelly C
Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California.
Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.
Cell Mol Gastroenterol Hepatol. 2025 Apr 17;19(8):101513. doi: 10.1016/j.jcmgh.2025.101513.
BACKGROUND & AIMS: FOLFOX, often used in patients with colorectal liver metastases, can cause sinusoidal obstruction syndrome (SOS) hindering subsequent treatment. S-adenosylmethionine (SAMe) is hepatoprotective and here we investigated whether it protects against FOLFOX-induced hepatotoxicity and defined the underlying mechanisms.
A murine model of FOLFOX-induced SOS examined the effect of SAMe and plasminogen-activating inhibitor-1 (PAI-1). In vitro studies included primary mouse and human hepatocytes, Kupffer cells, hepatic stellate cells, and liver sinusoidal endothelial cells.
SAMe cotreatment completely blocked the induction of markers increased in FOLFOX-induced SOS and protected against liver injury. The most up-regulated gene was Serpine1, which encodes for PAI-1. SAMe blocked FOLFOX-induced expression and activation of nuclear factor (NF)-κB, which is known to activate SERPINE1/Serpine1 promoters. Interestingly, FOLFOX failed to activate hepatic NF-κB or cause liver injury in Serpine1 knockout male mice. Treatment of mouse hepatocytes with recombinant PAI-1 induced NF-κB activation; conditioned media from recombinant PAI-1 or interleukin-1β-treated hepatocytes, but not exosomes, increased the expression of proinflammatory cytokines and Cd31 in Kupffer cells and liver sinusoidal endothelial cells, respectively, which were blocked by SAMe. FOLFOX and interleukin-1β induced interaction between PAI-1 with urokinase plasminogen activator receptor in mouse liver and hepatocytes, respectively, which was blocked by SAMe. Recombinant PAI-1 requires interaction with uPA for full activation of NF-κB in hepatocytes. Neutralizing antibody against PAI-1 blocked interleukin-1β-mediated p65/PAI-1 activation in hepatocytes.
FOLFOX treatment increased hepatocyte PAI-1 expression and liver injury, which were not observed in germline PAI-1 deficiency. Hepatocytes secrete PAI-1 to exert autocrine and paracrine effects to activate Kupffer cells and liver sinusoidal endothelial cells. SAMe protects against FOLFOX-mediated liver injury in part by inhibiting NF-κB activation and PAI-1 induction.
FOLFOX常用于治疗结直肠肝转移患者，可引发肝窦阻塞综合征（SOS），进而妨碍后续治疗。S-腺苷甲硫氨酸（SAMe）具有肝脏保护作用，我们在此研究其是否能预防FOLFOX诱导的肝毒性，并明确潜在机制。
采用FOLFOX诱导的SOS小鼠模型，研究SAMe和纤溶酶原激活物抑制剂-1（PAI-1）的作用。体外研究包括原代小鼠和人肝细胞、库普弗细胞、肝星状细胞及肝窦内皮细胞。
SAMe联合治疗完全阻断了FOLFOX诱导的SOS中升高的标志物的诱导，并预防了肝损伤。上调最明显的基因是Serpine1，其编码PAI-1。SAMe阻断了FOLFOX诱导的核因子（NF）-κB的表达和激活，已知NF-κB可激活SERPINE1/Serpine1启动子。有趣的是，在Serpine1基因敲除雄性小鼠中，FOLFOX未能激活肝脏NF-κB或导致肝损伤。用重组PAI-1处理小鼠肝细胞可诱导NF-κB激活；重组PAI-1或白细胞介素-1β处理的肝细胞的条件培养基（而非外泌体）分别增加了库普弗细胞和肝窦内皮细胞中促炎细胞因子和Cd31的表达，而SAMe可阻断这种增加。FOLFOX和白细胞介素-1β分别诱导了PAI-1与小鼠肝脏和肝细胞中尿激酶型纤溶酶原激活物受体的相互作用，而SAMe可阻断这种相互作用。重组PAI-1需要与尿激酶型纤溶酶原激活物相互作用才能在肝细胞中完全激活NF-κB。抗PAI-1中和抗体可阻断白细胞介素-1β介导的肝细胞中p65/PAI-1的激活。
FOLFOX治疗可增加肝细胞PAI-1表达和肝损伤，而在种系PAI-1缺乏的情况下未观察到这种情况。肝细胞分泌PAI-1以发挥自分泌和旁分泌作用，激活库普弗细胞和肝窦内皮细胞。SAMe部分通过抑制NF-κB激活和PAI-1诱导来预防FOLFOX介导的肝损伤。
