Splenectomy has been reported to improve liver fibrosis in patients with cirrhosis and hypersplenism. However, the mechanisms remain unclear. Tumor necrosis factor superfamily 14 (TNFSF14; also known as LIGHT) is highly expressed in the context of fibrosis and promotes disease progression in patients with fibrotic diseases such as pulmonary and skin fibrosis. Here, we determined whether splenectomy controls the production of LIGHT to improve liver fibrosis. Splenectomy reduced serum LIGHT levels in cirrhotic patients with hypersplenism and a ConA-induced liver fibrosis mouse model. Blocking LIGHT resulted in the downregulation of TGF-β1 in RAW264.7 cells. LIGHT treatment of RAW264.7 and JS1 cells in coculture regulated transforming growth factor-β1 (TGF-β1) expression through the activation of JNK signaling. Small interfering RNA-mediated silencing of lymphotoxin β receptor (LTβR) in macrophages resulted in pronounced decreases in the levels of fibrosis and αSMA in JS1 cells. These results indicated that LIGHT bound to LTβR and drove liver fibrosis in vitro. Blocking TGF-β1 abolished the effect of LIGHT in vitro. Furthermore, the administration of recombinant murine LIGHT protein-induced liver fibrosis with splenectomy, while blocking LIGHT without splenectomy improved liver fibrosis in vivo, revealing that the decrease in fibrosis following splenectomy was directly related to reduced levels of LIGHT. Thus, high levels of LIGHT derived from the spleen and hepatic macrophages activate JNK signaling and lead to increased TGF-β1 production in hepatic macrophages. Splenectomy attenuates liver fibrosis by decreasing the expression of LIGHT.

As a novel drug development paradigm, selective activation of prodrugs provides the potential for precise tumor chemotherapy, thereby presenting an opportunity for advancing cancer treatment. The combination of photodynamic therapy (PDT) and prodrug can enhance the therapeutic efficacy while simultaneously enabling real‐time monitoring of drug distribution and release. However, the tumor hypoxia microenvironment and the frequent high‐dose administration of prodrugs significantly impede therapeutic efficacy and escalate treatment‐related risks. Herein, a tumor microenvironment‐specific release prodrug is constructed, termed NBS‐2S‐5FU. Under the influence of glutathione (GSH), NBS‐2S‐5FU undergoes activation, leading to the release of photosensitizer NBS and chemotherapeutic agent 5‐FU derivatives. Under irradiation, NBS produces sufficient superoxide radical () while 5‐FU derivatives inhibit DNA biosynthesis, thereby effectively suppressing tumor growth at low doses. Subsequent in vivo studies utilizing NBS‐2S‐5FU liposomes exhibit outstanding anti‐cancer effectiveness. This study highlights a promising direction for advancing combined prodrugs that integrate PDT and chemotherapy.

Liver cirrhosis is prognostically associated with poor life expectancy owing to subsequent liver failure. Thus, understanding liver regeneration processes during cirrhotic injury is highly important. This study explored the role of macrophage heterogeneity in liver regeneration following splenectomy. We collected detailed clinical information from 54 patients with decompensated cirrhosis before and after splenectomy. Obvious liver regeneration was observed after splenectomy in cirrhotic patients. Single-cell RNA sequencing (scRNA-seq) was performed on three paired liver tissues from patients before and after surgery to explore the immune microenvironment map and the characteristics of liver regeneration-associated macrophages (RAMs). scRNA-seq analysis revealed that the composition of hepatic immune cells changed after splenectomy; among these changes, the proportion of CD300E⁺ RAMs significantly increased after surgery, and high expression levels of functional genes associated with cell proliferation promoted liver regeneration. Moreover, a mouse model of carbon tetrachloride-induced cirrhosis and a coculture system consisting of primary bone marrow-derived macrophages and hepatocytes were established for validation. We observed a similar phenomenon of liver regeneration in cirrhotic mice and further confirmed that CD300E⁺ monocyte-derived macrophages facilitated hepatocyte NAD⁺ synthesis via the secretion of NAMPT, which subsequently promoted hepatocyte proliferation. This study characterized the hepatic immune microenvironment in patients with cirrhosis following splenectomy. Our findings demonstrated that CD300E⁺ macrophages play a crucial role in remodeling the hepatic immune microenvironment after splenectomy, thereby promoting liver regeneration in patients with decompensated cirrhosis. CD300E⁺ macrophages are anticipated to emerge as a novel therapeutic strategy for the treatment of liver cirrhosis.

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Background: Portal veinous system thrombosis (PVST) is a common complication after laparoscopic splenectomy plus esophagogastric devascularization (LSED). Anticoagulation therapy was still in debate in LSED perioperation. This study aimed to determine the postoperative risk factors of PVST, the efficacy and safety of the anticoagulation therapy after LSED procedure, and the potential impact of anticoagulation on patients' liver function and overall survival (OS). Methods: Three hundred patients who underwent LSED were retrospectively enrolled and analyzed in the study. The characteristics of patients, perioperative parameters, risk of PVST, and long-term follow-up data were recorded and analyzed. Results: One hundred eighty six of 300 patients received perioperative anticoagulation therapy (p-AT) postoperation, while 114 patients did not receive p-AT (non-p-AT). The non-p-AT group had more intraoperative blood loss, PVST, longer abdominal drain days, and postoperative hospital stays separately compared with the p-AT group. No significant difference of postoperative complications was found between the two groups. In the 1-year follow-up postoperation, both groups had great improvement in hypersplenism and the portal vein hemodynamics. During the 10-year follow-up period, the incidence of PVST was significantly higher in the non-p-AT group than in the p-AT group. Anticoagulation therapy, sex, variceal hemorrhage history, portal vein diameter, and portal vein velocity were the independent prognostic factors determined by the Cox regression analysis for PVST. The thrombosis-free survival rate (P = .002), recurrent hemorrhage-free survival rate (P < .01), and the OS rate (P < .01) were significantly lower in the non-p-AT group than in the p-AT group. Conclusions: The initiate use of anticoagulation therapy in postoperation of LSED is effective and safe in cirrhotic patients. The anticoagulation therapy after LSED will help decrease portal vein thrombosis, the rebleeding rate, and extend the OS of the patients, especially among women, with variceal hemorrhage history, high portal vein diameter, and low portal vein velocity.

Introduction Laparoscopic splenectomy and esophagogastric devascularization (LSED) is becoming increasingly popular in the treatment of esophageal-fundic variceal bleeding with portal hypertension (PHT) in China, and its high safety and minimal trauma have been proven. Fast-track (FT) surgery...