The 12-lipoxygenase (12-LOX)/12-hydroxyeicosatetraenoic acid (12-HETE) pathway is associated with various tumors. M2 macrophages in the tumor microenvironment promote tumorigenesis and progression. However, the role of the 12-LOX/12-HETE/G protein-coupled receptor 31 (GPR31) metabolic pathway and its relationship with M2 macrophages remains unclear in pancreatic cancer (PC).
The expression levels of 12-LOX, GPR31, and 12-HETE were detected in PC and mouse PC models using western blot and enzyme-linked immunosorbent assays (ELISA). In vivo and in vitro experiments were conducted using the 12-LOX inhibitor ML355 to investigate the role of the 12-LOX/12-HETE/GPR31 metabolic pathway in M2 macrophage polarization and tumor progression through flow cytometry, reverse transcription polymerase chain reaction (RT-PCR), 5-Ethynyl-20-deoxyuridine (EdU) assays, and Transwell experiments.
The 12-LOX/12-HETE/GPR31 metabolic pathway is expressed actively in PC. Inhibition of 12-LOX in a mouse model of pancreatic cancer suppressed the expression of this metabolic pathway, retarded tumor growth, and reduced the polarization of macrophages towards the M2 type. In vitro, co-culturing PC cell line PANC-1 with macrophages and selectively inhibiting 12-LOX influenced the proliferation, migration, and invasion of PC cells. Inhibiting 12-LOX did not suppress the function of individual PC cells, but it inhibited the development of PC cells co-cultured with macrophages. Moreover, inhibiting 12-LOX reduced the co-cultured M2 macrophages.
This study, through in vivo and in vitro experiments, reveals that the 12-LOX/12-HETE/GPR31 metabolic pathway affects the growth, migration, and invasion of PC by modulating M2 macrophage polarization patterns.
©2025 Yang et al.

The transcription factor AP-2α plays a crucial role in the control of tumor development and progression, and suppresses the proliferation and migration of hepatocellular carcinoma (HCC). However, the detailed function and mechanisms of AP-2α in the pathogenesis of HCC are still elusive. In the current study, we investigated the role of AP-2α regulation in liver injury-mediated HCC development. Downregulation of Tfap2a expression was found in the livers of DEN/CCl4-induced fibrosis and HCC mouse model. Hepatocyte (Alb-Cre), hepatic stellate cell (HSC) (Lrat-Cre) and macrophage (LysM-Cre) specific Tfap2a knockout mice were generated, respectively. Conditional knockout of Tfap2a was able to promote hepatic steatosis in Tfap2aΔHep and Tfap2aΔMΦ mice, but not in Tfap2aΔHSC mice fed with normal chow. Tfap2aΔHep and Tfap2aΔMΦ mice treated with DEN/CCl4 for 6 months increased tumor burden compared to Tfap2a flox controls. Tfap2a-deleted macrophages or hepatocytes could enhance lipid droplet (LD) accumulation in hepatocytes. Mechanistically, AP-2α binds to the promoter regions of SREBP1/ACC/FASN and inhibits hepatic lipid de novo synthesis. Deletion of Tfap2a in macrophages enhances polarization of M1 macrophages with increased iNOS expression but decreased CD206 expression, which resulted in increased pro-inflammatory cytokines and decreased anti-inflammatory factors, especially the hepatoprotective factor IL-10. The m6A modification writer WTAP could reduce the mRNA stability of AP-2α in a reader YTHDC1-dependent manner, whereas knockdown of WTAP or YTHDC1 enhances AP-2α expression and decreases lipid accumulation in HCC cells. Clinically, AP-2α expression negatively correlates with the expression of FASN, WTAP, YTHDC1 and the development of liver disease. Taken together, hepatocyte- or macrophage-specific deletion of Tfap2a promotes hepatic steatosis, fibrosis, and the development of HCC. These results suggest that AP-2α has been identified as a novel therapeutic target in fibrosis and inflammation-related HCC, exerting anti-lipogenesis, anti-inflammatory, and anti-tumor multi-roles.
© 2025. The Author(s).

Periodontitis, when exacerbated by diabetes, is characterized by increased M1 macrophage polarization and decreased M2 polarization. O-linked β-N-acetylglucosamine (O-GlcNAcylation), catalyzed by O-GlcNAc transferase (OGT), promotes inflammatory responses in diabetic periodontitis (DP). Additionally, p38 mitogen-activated protein kinase regulates macrophage polarization. However, the interplay between OGT, macrophage polarization, and p38 signaling in the progression of DP remains unexplored.
To investigate the effect of OGT on macrophage polarization in DP and its role in mediating O-GlcNAcylation of p38.
For in vivo experiments, mice were divided into four groups: Control, DP model, model + short hairpin (sh) RNA-negative control, and model + sh-OGT. Diabetes was induced by streptozotocin, followed by ligation and lipopolysaccharide (LPS) administration to induce periodontitis. The impact of OGT was assessed by injecting sh-OGT lentivirus. Maxillary bone destruction was evaluated using micro-computed tomography analysis and tartrate-resistant acid phosphatase staining, while macrophage polarization was determined through quantitative real-time polymerase chain reaction (qPCR) and immunohistochemistry. For in vitro experiments, RAW264.7 cells were treated with LPS and high glucose (HG) (25 mmol/L D-glucose) to establish a cell model of DP. OGT was inhibited by OGT inhibitor (OSMI4) treatment and knocked down by sh-OGT transfection. M1/M2 polarization was analyzed using qPCR, immunofluorescence, and flow cytometry. Levels of O-GlcNAcylation were measured using immunoprecipitation and western blotting.
Our results demonstrated that M1 macrophage polarization led to maxillary bone loss in DP mice, associated with elevated O-GlcNAcylation and OGT levels. Knockdown of OGT promoted the shift from M1 to M2 macrophage polarization in both mouse periodontal tissues and LPS + HG-induced RAW264.7 cells. Furthermore, LPS + HG enhanced the O-GlcNAcylation of p38 in RAW264.7 cells. OGT interacted with p38 to promote its O-GlcNAcylation at residues A28, T241, and T347, as well as its phosphorylation at residue Y221.
Inhibition of OGT-mediated p38 O-GlcNAcylation deactivates the p38 pathway by suppressing its self-phosphorylation, thereby promoting M1 to M2 macrophage polarization and mitigating DP. These findings suggested that modulating macrophage polarization through regulation of O-GlcNAcylation may represent a novel therapeutic strategy for treating DP.
©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.

Diabetic wounds are serious chronic complications of diabetes and can lead to amputation and death. Although considerable progress has been made in drugs and materials for treating it, it's still an urgent clinical problem as the materials and drugs have potential therapeutic drawbacks, such as low delivery efficiency and poor tissue permeability. To promote diabetic wound healing, a composite of thonningianin A (TA)-loaded chitosan nanoparticles (CNPS) encapsulated by a Pluronic F-127 (PF-127) hydrogel (TA-CNPS-PF) was developed in this study.
TA-CNPS was prepared by ionic gelation method and TA-CNPS was thoroughly dispersed into PF-127 hydrogel to prepare TA-CNPS-PF. The particle size, hydrogel structure, encapsulation ratio, release ratio, antimicrobial properties of TA-CNPS-PF were determined and the effect of TA-CNPS-PF on diabetic wounds was assessed. The effect of TA on macrophage polarization was also examined in vitro.
The particle size was approximately 100 nm of TA-CNPS-PF and the hydrogel had a homogeneous three-dimensional reticulation structure. The encapsulation efficiency of TA in the CNPS were 99.3% and the release ratio of TA-CNPS-PF was approximately 86% and has antimicrobial properties. TA-CNPS-PF promoted diabetic wound healing significantly. Histopathology confirmed that TA-CNPS-PF promoted complete re-epithelialization and adequate collagen deposition. TA promoted the polarization of M1 macrophages into M2 macrophages via light microscopy, immunocytometry and flow cytometry. TA-CNPS-PF also promoted an increase in the number of M2 macrophages in diabetic wounds.
TA promotes diabetic wound healing by promoting the polarization of M1 macrophages into M2 macrophages and TA-CNPS-PF has good antimicrobial activity and a good drug release ratio in this study, which provides a new direction for the treatment of diabetic wounds and is expected to be highly advantageous in clinical diabetes wound therapy.
© 2024 Lin et al.

Abnormal glucose metabolism in microglial is closely associated with Alzheimer's disease (AD). Reprogramming of microglial glucose metabolism is centered on regulating the way in which microglial metabolize glucose to alter microglial function. Therefore, reprogramming microglial glucose metabolism is considered as a therapeutic strategy for AD. Huanshaodan (HSD) is a Chinese herbal compound which shows significant efficacy in treating AD, however, the precise mechanism by which HSD treats AD remains unclear. This study is aim to investigate whether HSD exerts anti-AD effects by regulating the metabolic reprogramming of microglial through the mTOR/HIF-1α signaling pathway. SAMP8 mice and BV2 cells were used to explore the alleviative effect of HSD on AD and the molecular mechanism in vivo and in vitro. The pharmacodynamic effects of HSD was evaluated by behavioral tests. The pathological deposition of Aβ in brain of mice was detected by immunohistochemistry. ELISA method was used to measure the activity of HK2 and the expression of PKM2, IL-6 and TNF-α in hippocampus and cortex tissues of mice. Meanwhile, proteins levels of p-mTOR, mTOR, HIF-1α, CD86, Arg1 and IL-1β were detected by Western-blot. LPS-induced BV2 cells were treated with HSD-containing serum. The analysis of the expression profiles of the CD86 and CD206 markers by flow cytometry allows us to distinguish the BV2 polarization. Glucose, lactic acid, ATP, IL-6 and TNF-α levels, as well as lactate dehydrogenase and pyruvate dehydrogenase activities were evaluated in the BV2. Western-blot analysis was employed to detect mTOR, p-mTOR, HIF-1α and IL-1β levels in BV2. And the mTOR agonist MHY1485 (MHY) was chosen to reverse validate. In this study, it is found that HSD improved cognitive impairment in SAMP8 mice and reduced Aβ deposition, suppressed the levels of glycolysis and neuroinflammation in mice. In LPS-induced BV2 cells, HSD also regulated glycolysis and neuroinflammation, and suppressed the mTOR/HIF-1α signaling pathway. More importantly, these effects were reversed by MHY. It is demonstrated that HSD regulated microglial glucose metabolism reprogramming by inhibiting the mTOR/HIF-1α signaling pathway, alleviated neuroinflammation, and exerted anti-AD effects. This study provided scientific evidence for the clinical application of HSD for treating AD.
Copyright © 2024 Shang, Su, Ma, Li, Wang, Ma, Song and Zhang.