Targeting OXCT1-mediated ketone metabolism reprograms macrophages to promote antitumor immunity via CD8+ T cells in hepatocellular carcinoma.

BACKGROUND & AIMS: The liver is the main organ of ketogenesis, while ketones are mainly metabolized in peripheral tissues via the critical enzyme 3-oxoacid CoA-transferase 1 (OXCT1). We previously found that ketolysis is reactivated in hepatocellular carcinoma (HCC) cells through OXCT1 expression to promote tumor progression; however, whether OXCT1 regulates antitumor immunity remains unclear. METHODS: To investigate the expression pattern of OXCT1 in HCC in vivo, we conducted multiplex immunohistochemistry experiments on human HCC specimens. To explore the role of OXCT1 in mouse HCC tumor-associated macrophages (TAMs), we generated LysMcreOXCT1f/f (OXCT1 conditional knockout in macrophages) mice. RESULTS: Here, we found that inhibiting OXCT1 expression in tumor-associated macrophages reduced CD8+ T-cell exhaustion through the succinate-H3K4me3-Arg1 axis. Initially, we found that OXCT1 was highly expressed in liver macrophages under steady state and that OXCT expression was further increased in TAMs. OXCT1 deficiency in macrophages suppressed tumor growth by reprogramming TAMs toward an antitumor phenotype, reducing CD8+ T-cell exhaustion and increasing CD8+ T-cell cytotoxicity. Mechanistically, high OXCT1 expression induced the accumulation of succinate, a byproduct of ketolysis, in TAMs, which promoted Arg1 transcription by increasing the H3K4me3 level in the Arg1 promoter. In addition, pimozide, an inhibitor of OXCT1, suppressed Arg1 expression as well as TAM polarization toward the protumor phenotype, leading to decreased CD8+ T-cell exhaustion and slower tumor growth. Finally, high expression of OXCT1 in macrophages was positively associated with poor survival in patients with HCC. CONCLUSIONS: In conclusion, our results demonstrate that OXCT1 epigenetically suppresses antitumor immunity, suggesting that suppressing OXCT1 activity in TAMs could be an effective approach for treating liver cancer. IMPACT AND IMPLICATIONS: The intricate metabolism of liver macrophages plays a critical role in shaping hepatocellular carcinoma progression and immune modulation. Targeting macrophage metabolism to counteract immune suppression presents a promising avenue for hepatocellular carcinoma treatment. Herein, we found that the ketogenesis gene OXCT1 was highly expressed in tumor-associated macrophages (TAMs) and promoted tumor growth by reprogramming TAMs toward a protumor phenotype. Pharmacological targeting or genetic downregulation of OXCT1 in TAMs enhances antitumor immunity and slows tumor growth. Our results suggest that suppressing OXCT1 activity in TAMs could be an effective approach for treating liver cancer.

High Mobility Group Box 1 Ameliorates Cognitive Impairment in the 3×Tg-AD Mouse Model.

BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia. Studies indicate that neuroinflammation plays an important role in the pathophysiology of AD. High-mobility group box 1 (HMGB1) is an important chromatin protein. It can be secreted by immune cells and passively released from damaged cells to promote inflammation. HMGB1 also can recruit stem cells and promote their proliferation and tissue repairing. However, the role of HMGB1 in the progression of AD is currently unknown. OBJECTIVE: The aims were to investigate the effect of HMGB1 on the AD-related pathologies and cognitive function using 3×Tg-AD mouse model. METHODS: Female 5-month-old 3×Tg-AD mice were intracerebroventricularly injected with 4.5 µg of HMGB1 or with saline as a control. The levels of interesting protein were assessed by western blots or immunofluorescence. The effect of HMGB1 on the cognitive function was evaluated by one-trial novel object recognition test and Morris water maze. RESULTS: Intracerebroventricular injection of recombinant HMGB1 ameliorated cognitive impairment in 5-6-month-old 3×Tg-AD mice. The levels of synapsin 1, synaptophysin, MAP2, NeuN, and phosphorylated CREB were increased in HMGB1-treated 3×Tg-AD mouse brains. HMGB1 decreased intracellular amyloid-ß level but did not affect tau phosphorylation. HMGB1 treatment also promoted neurogenesis in the dentate gyrus and increased the level of GFAP in the 3×Tg-AD mouse brains. CONCLUSION: These results reveal a novel function of HMGB1 in enhancing neuroplasticity and improving cognitive function in 3×Tg-AD mice.

Effect of pre-transplantation hemoglobin concentration on prognosis of renal transplant recipients.

BACKGROUND: For the renal transplant recipients, anemia is one of the common complications and becomes a major medical issue before transplantation. Haemoglobin (Hb) is used as a prognostic indicator, although the optimal pre-transplantation Hb concentration associated with positive prognosis is still controversial. The aim of this study was to detect the optimal Hb concentration on predicting the graft survival and function. METHODS: A retrospective cohort study was conducted by reviewing the medical records of the patients who received renal transplantations at our center from January 2004 to June 2008. Patients were divided into two groups: high Hb group (≥ 100 g/L, n = 79) and low Hb group (< 100 g/L, n = 63). There was no significant difference between the two groups regarding sex, age, blood type and tissue types. Renal function among the two groups was measured and compared. Panel reacting antigens (PRA) of all the recipients were negative. The effect of preoperative hemoglobin concentration on the postoperative renal function recovery in both groups was further analyzed. RESULTS: A total of 14 acute rejection episodes occurred, including 5 patients in the high Hb group (7.9%) and 9 in the low Hb group (11.4%, P > 0.05). The serum creatinine level at one-year post-transplantation of the low Hb group was significantly higher than that of the high Hb group ((117.8 ± 36.3) µmol/L vs. (103.1 ± 35.5) µmol/L, P < 0.05). For one-year actuarial patient and graft survival, incidence of delayed graft function (DGF), serum creatinine concentrations at 1, 3, 6 months post-transplantation, the incidence of cytomegalovirus (CMV) infection, post-transplantation anemia (PTA) and post-transplantation diabetes mellitus (PTDM) of both groups, there were no statistically significant differences. CONCLUSION: Pre-transplantation Hb concentration has significant effect on one-year creatinine concentration, but can not significantly affect acute rejection episodes, DGF, PTA, CMV infection and PTDM.