Transmembrane 4 L six family member 1 (TM4SF1) is highly expressed and contributes to the progression of various malignancies. However, how it modulates hepatocellular carcinoma (HCC) progression and senescence remains to be elucidated.
TM4SF1 expression in HCC samples was evaluated using immunohistochemistry and flow cytometry. Cellular senescence was assessed through SA-β-gal activity assays and Western blot analysis. TM4SF1-related protein interactions were investigated using immunoprecipitation-mass spectrometry, co-immunoprecipitation, bimolecular fluorescence complementation, and immunofluorescence. Tumor-infiltrating immune cells were analyzed by flow cytometry. The HCC mouse model was established via hydrodynamic tail vein injection.
TM4SF1 was highly expressed in human HCC samples and murine models. Knockdown of TM4SF1 suppressed HCC proliferation both in vitro and in vivo, inducing non-secretory senescence through upregulation of p16 and p21. TM4SF1 enhanced the interaction between AKT1 and PDPK1, thereby promoting AKT phosphorylation, which subsequently downregulated p16 and p21. Meanwhile, TM4SF1-mediated AKT phosphorylation enhanced PD-L1 expression while reducing major histocompatibility complex class I level on tumor cells, leading to impaired cytotoxic function of CD8+ T cells and an increased proportion of exhausted CD8+ T cells. In clinical HCC samples, elevated TM4SF1 expression was associated with resistance to anti-PD-1 immunotherapy. Targeting TM4SF1 via adeno-associated virus induced tumor senescence, reduced tumor burden and synergistically enhanced the efficacy of anti-PD-1 therapy.
Our results revealed that TM4SF1 regulated tumor cell senescence and immune evasion through the AKT pathway, highlighting its potential as a therapeutic target in HCC, particularly in combination with first-line immunotherapy.

The differentiation of Th17 and iTreg is tightly associated with fatty acid metabolism. TGFβ1-induced iTreg differentiation from Th0 relies on fatty acid oxidation (FAO), whereas IL-6 with TGFβ1 shifts metabolism to Th17-preferred fatty acid synthesis (FAS). However, how IL-6 reprograms fatty acid metabolism remains unclear. Here, we unveiled that TGFβ1-activated JNK is recruited to the Klhl25 promoter by NF-YA. JNK then phosphorylates histone H3 at Ser10 to activate Klhl25 transcription, leading to the ubiquitination-dependent degradation of ATP-citrate lyase (ACLY) and the switch from FAS to FAO, which supports iTreg generation. Whereas, upon IL-6 signaling, NF-YA is phosphorylated by ERK, losing its DNA binding ability, which shuts off TGFβ1-JNK-mediated Klhl25 transcription and ACLY ubiquitination, thereby increasing FAS and supporting Th17 differentiation. This study demonstrated that KLHL25-ACLY module functions as a switch in response to TGFβ1 and IL-6 signals, playing a decisive role in the fate determination of iTreg/Th17 differentiation.
© 2025. The Author(s).

Myricetin is a bioactive compound in many edible plants. We have previously demonstrated that myricetin could significantly protect mice against colitis by regulating Treg/Th17 balance, while underlying mechanism remains unclear. The current study aimed to unravel the potential regulating mechanism of myricetin.
The concentrations of 22 amino acids in colon were determined using HPLC-MS/MS and principal component analysis (PCA) was performed on the data. MetaboAnalyst was used to detect potential biological pathway influenced by myricetin. The results were further verified using qPCR, molecular docking method, and AhR inhibitor.
Studies had found that the biosynthesis of phenylalanine, tyrosine, and tryptophan; phenylalanine metabolism; and histidine metabolism were the most important pathways related to myricetin. Therefore, the aryl hydrocarbon receptor (AhR), which is closely related to the metabolism of tryptophan, phenylalanine, and tyrosine, was postulated to be the underlying signaling pathways. Furthermore, administration of myricet in significantly increased the relative expressions of CYP1A1 and CYP1B1, whereas AhR inhibitor abolished the amelioration of myricetin on DSS-induced colitis. Moreover, AhR inhibitor weakened the regulatory effect of myricetin on Treg/Th17 balance. Furthermore, the results obtained by the molecular docking method speculated that myricetin could bind to AhR as a ligand and activate AhR.
The results suggested that myricetin could exert its protection against dextran sulfate sodium (DSS)-induced colitis by activating AhR signaling pathway.
© 2025 Tao Xu et al.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment and significantly improved outcomes for patients with certain malignancies. However, immunotherapy with ICIs is only effective in a subset of patients and the gut microbiota have been identified as an important factor associated with response to ICI therapy. Polysaccharides from sea cucumber (Stichopus japonicus) (SCP) have been shown to modulate the gut microbiota and exhibit beneficial health functions, but whether SCP could synergize with anti-PD1 immunotherapy remains unexplored. In this study, mice with ICI-sensitive MC38 tumors were treated with anti-PD1 antibody after supplementation with or without SCP to examine the potential impact of SCP on the efficacy of immunotherapy. SCP strongly amplified the anti-tumor activity of anti-PD1 in MC38 tumor-bearing mice. Flow cytometry and immunohistological staining demonstrated that SCP treatment increased cytotoxic CD8+ T lymphocytes while decreasing regulatory Foxp3+ CD4+ T lymphocytes. Gut microbiota and metabolomic analysis revealed that SCP modulated the microbiota and increased the abundance of certain metabolites such as indole-3-carboxylic acid. Furthermore, fecal microbiota transplantation experiments justified that the synergistic effect of SCP with anti-PD1 was partially mediated through the gut microbiota. Mice receiving microbiota from SCP-treated mice showed a boosted response to anti-PD1, along with enhanced anti-tumor immunity. These findings indicate that SCP could be utilized as a dietary strategy combined with anti-PD1 therapy to achieve improved outcomes in patients.

Chronic prostatitis and Pelvic Pain syndrome (CP/CPPS) is an autoimmune inflammatory disease characterized by pelvic or perineal pain and infiltration of inflammatory cells in the prostate. C-X-C chemokine receptor type 7 (CXCR7) is an atypical chemokine receptor that has been shown to play a key role in inflammatory processes in prostate cancer. However, the role of CXCR7 in autoimmune prostate and immune regulation in CP/CPPS along with the mechanism of action for CXCR7 remains unclear. In this study, a mouse model of experimental autoimmune prostatitis (EAP) was constructed by subcutaneous injection of antigen, and CXCR7 agonist was administered to investigate the effects of CXCR7 on the proportion of immune cells and fibrosis in CP/CPPS. Western blotting, immunohistochemical staining and immunofluorescence, flow cytometry, and masson's trichrome staining were used to study the regulatory mechanisms of CXCR7 in immune regulation. CXCR7 agonists can significantly reduce pain and prostatic inflammation, and in vivo flow cytometry studies showed that the antagonists restored the imbalance of the Th17/Treg cell ratio. To elucidate the potential mechanisms by which CXCR7 influences the pathogenesis of CP/CPPS, we conducted simultaneous RNA-seq and non-targeted metabolome sequencing. Our findings suggest that CXCR7 agonists alleviate fibrosis in autoimmune prostatitis by inhibiting the TGFβ/SMAD pathway. This study provides the foundation to target the immunological function of CXCR7 as a novel therapy for CP/CPPS.
Copyright © 2024. Published by Elsevier B.V.