ABSTRACT Hepatocellular carcinoma (HCC), a lethal form of liver cancer, continues to show rising mortality rates despite advancements in immunotherapies. This highlights the need for more effective treatments. Recent studies linked the presence of B cells within human tumors, including HCC, to improved responses to immunotherapy and better prognoses. Specifically, tumor‐infiltrating B cells have been associated with reduced cancer cell proliferation, suggesting that B cell‐mediated responses may be harnessed as a potential therapeutic strategy against HCC. However, in advanced HCC, IL‐10‐producing regulatory B cells accumulate and promote tumor growth. These paradoxical findings on B cells in human HCC highlight the necessity for clarifying the specific functions of B cells in HCC development to develop B cell‐targeted therapies. To investigate the role of B cells in HCC, we used B cell‐deficient (muMT) mice and anti‐CD20 antibodies to deplete B cells in WT mice. In both systems, we observed a strong protection against liver tumor formation upon HCC induction, indicating the presence of a potent anti‐tumor effect in the absence of B cells before HCC induction. Additionally, depletion of B cells after tumor foci have formed in the liver at later stage of HCC also potently suppressed tumor growth. Functionally, depletion of CD4 + and CD8 + T cells partially restored susceptibility to tumor growth, suggesting that B cell depletion suppresses HCC development partly through enhanced T cell‐mediated immunity. These findings reveal an underappreciated tumor‐suppressing effect of B cells in HCC and suggest that targeting the mechanisms of B cell suppression may boost anti‐tumor responses in HCC.
ABSTRACT HSPD1 is an important chaperone protein whose primary function is to assist the correct folding of mitochondrial proteins and its co‐chaperone. It exerts multiple biological effects, including participation in protein homeostasis maintenance, stress resistance, and cellular protection. However, whether Hspd1 modulates the proliferation and differentiation of C2C12 cells remains unclear. In this study, we observed that overexpression or knockdown of the Hspd1 gene increased or decreased C2C12 cell proliferation, respectively, whereas differentiation exhibited the opposite trend. Furthermore, co‐immunoprecipitation coupled with mass spectrometry identified several putative HSPD1‐interacting partners. Functional assays revealed that altering Hspd1 expression correlated with changes in the expression of mitochondrial morphology‐related genes, transcripts of components of the tricarboxylic acid cycle and electron transport chain, as well as intracellular ATP levels. Although these results are consistent with the hypothesis that HSPD1‐associated mitochondrial alterations may contribute to myoblast behavior, they do not exclude other potential mechanisms. Collectively, this study provides correlative evidence linking Hspd1 to mitochondrial regulation in C2C12 cells and underscores the necessity for further mechanistic dissection, including rescue experiments to establish causality.
ABSTRACT Cementum shares similar characteristics with bone in terms of biochemical composition. Recent studies have reported that glycolysis is the main energy source driving osteoblast differentiation, but the role of glycolysis in cementoblast differentiation remains elusive. Previously, we found Sirtuin 6 (SIRT6) suppressed cementoblast differentiation and mineralization via inhibiting glucose transporter 1 (GLUT1), indicating that glycolysis may also be required for cementogenesis. However, the underlying mechanisms remain largely unknown. In this study, we observed that the expression of glycolytic enzymes increased progressively during cementoblast differentiation. Measurements of extracellular acidification rate, glucose uptake, lactate release, and gain‐and‐loss of function demonstrated that overexpressing SIRT6 in immortalized mouse cementoblasts (OCCM‐30) suppressed cementoblast glycolysis. Mechanistically, chromatin immunoprecipitation assay results revealed that SIRT6 inhibits insulin receptor substrate 2 (IRS2) transcription by deacetylating histone H3 at lysine K9 (H3K9). Overexpression of IRS2 promoted OCCM‐30 glycolysis and mineralization through phosphoinositide 3‐kinase (PI3K)/protein kinase B (AKT) signaling pathway, whereas SIRT6 significantly inhibited PI3K/AKT pathway activity. Overall, our results demonstrate that SIRT6 inhibits IRS2 transcription by deacetylating histone H3K9, thereby reducing PI3K/AKT signaling‐induced glycolysis and suppressing cementoblast mineralization.
ABSTRACT Ischemia reperfusion (IR) injury is a major contributor to tissue damage and organ dysfunction following ischemic events and clinical interventions such as thrombolysis, revascularization, and transplantation, yet effective pharmacological strategies to limit this injury remain limited. Bromodomain‐containing protein 4 (BRD4), an epigenetic reader that recognizes acetylated lysine residues to drive super‐enhancer‐associated transcription. Upregulated BRD4 has emerged as a key regulator of the inflammatory, endothelial, and cell death pathways underlying post‐IR injury pathophysiology. Preclinical evidence across cerebral, cardiac, renal, and hepatic IR injury models indicates that BRD4 hyperactivation amplifies NFκB‐dependent inflammatory signaling, while its pharmacological or genetic inhibition confers substantial tissue protection. This review synthesizes current mechanistic understanding of BRD4 in IR injury pathogenesis, evaluates emerging BET/BRD4‐targeted therapeutic strategies, and outlines key translational challenges for advancing epigenetic pharmacology toward clinical application in IR‐associated disorders.
ABSTRACT Legg‐Calvé‐Perthes disease (LCPD) causes malformations of femoral head in children, which presents as a treatment challenge due to its unclear pathogenesis. This study aimed to investigate the influence of circCDR1as on LCPD and its related mechanisms. An in vivo LCPD model was established in spontaneously hypertensive rats (SHRs) and HMGB1‐stimulated chondrocytes were used to mimic LCPD in vitro. We found that circCDR1as was up‐regulated, while miR‐671‐5p was down‐regulated in LCPD patients, which exhibited a negative correlation. Depletion of circCDR1as restored the proliferation and inhibited ‐ferroptosis of HMGB1‐exposed chondrocytes, Mechanistically, circCDR1as silencing increased miR‐671‐5p expression that targeted NCOA4 mRNA to disrupt the NCOA4‐FTH1 interaction‐mediated ferritinophagy. Moreover, treatment with conditioned medium (CM) of circCDR1as‐silenced chondrocytes repressed M1 macrophage polarization via enhancing miR‐671‐5p expression that subsequently targeted TLR4 mRNA to inactivate TLR4/NF‐κB pathway. FUS was responsible for circCDR1as biogenesis via the direct binding to pre‐CDR1as mRNA. Collectively, chondrocyte ferroptosis was triggered by FUS‐activated circCDR1as via sponging miR‐671‐5p to enhance NCOA4‐FTH1 interaction‐mediated ferritinophagy, which resulted in M1 macrophage reprogramming via activating the TLR4/NF‐κB pathway, thus promoting LCPD development.
