ABSTRACT Curcumin, a selective histone acetyltransferase p300 inhibitor, demonstrates to attenuate liver injury. However, the precise molecular mechanisms underlying its epigenetic regulation of metabolic‐inflammatory pathways in hepatocytes remain incompletely understood. Here, we demonstrated that curcumin alleviated LPS/ d ‐galactosamine‐induced liver injury characterized by serum ALT/AST hyperactivities, histopathological lesions, and intrahepatic lipid accumulation, in mice. Curcumin suppressed hepatic overphosphorylation of IRS1 at Ser 307 and IRS2 at Ser 731 . It also attenuated mRNA overexpression of sterol regulatory element‐binding protein 1c and fatty acid synthase. Additionally, curcumin inhibited overphosphorylation of phosphoinositide 3‐kinase p85α at Tyr 607 , mammalian target of rapamycin at Ser 2448 , IκB kinase α/β at Ser 176/180 , and nuclear factor κB at Ser 536 . Importantly, immunofluorescence, Western blot, and ELISA analyses demonstrated that curcumin reduced cytoplasmic p300 overaccumulation and hyperactivity while it restored nuclear p300 decrease and hypoactivity. These effects were validated in TNF‐α‐stimulated hepatocytes. Curcumin reestablished p300 homeostasis by normalizing nucleo‐cytoplasmic shuttling dynamics and prolonging nuclear retention. Colocalization analysis using Pearson's coefficient showed that curcumin reversed TNF‐α‐induced increase in colocalization ratio of cytoplasmic p300 to insulin receptor substrate (IRS) 1 and IRS2. Our findings suggest that curcumin corrects hepatocyte compartment‐specific p300 dysregulation to decouple insulin resistant‐lipogenic‐inflammatory crosstalk in mitigation of liver injury in mice.
ABSTRACT Adipogenin ( Adig ) is a lipid droplet–associated protein that promotes lipid droplet growth. CCAAT/enhancer‐binding protein α (C/EBPα) is a transcription factor enriched in white adipose tissue and liver and is a key regulator of hepatic gene expression. In this study, we investigated the molecular mechanism by which C/EBPα regulates Adig gene expression in the liver of type 2 diabetic model ( ob/ob ) mice. Although hepatic C/EBPα expression levels were comparable between control and ob/ob mice, both Adig mRNA levels and the putative ADIG signal were significantly elevated in the fatty liver of ob/ob mice. This induction of Adig was markedly repressed by liver‐specific C/EBPα deficiency. Analysis of publicly available chromatin immunoprecipitation sequencing (ChIP‐seq) data revealed a C/EBPα‐binding peak within the Adig promoter region in the mouse liver. Within this peak, we identified a putative C/EBP response element ( Adig ‐CEBPRE, located at positions −87 to −79) that was relatively well conserved across multiple species, suggesting an evolutionarily conserved role of C/EBPα in Adig regulation. Reporter assays demonstrated that luciferase activity driven by Adig ‐CEBPRE was significantly induced by either C/EBPα or C/EBPβ, whereas this induction was abolished upon deletion of Adig ‐CEBPRE. Collectively, these findings indicate that Adig is a novel C/EBPα target gene in the steatotic liver of ob/ob mice, providing a mechanistic link between hepatic transcriptional regulation and lipid droplet homeostasis.
ABSTRACT The vacuolar ATPase (V‐ATPase) is essential for lysosomal acidification and autophagy, and its activity is regulated by nutrient‐sensitive reversible assembly of its V1 and Vo domains. While mTORC1 is known to inhibit V‐ATPase assembly, the precise molecular mechanisms remain incompletely understood. Here, using TurboID‐based proximity labeling and quantitative mass spectrometry, we identified the R2TP complex subunits RPAP3 and PIH1D1 as novel autophagy‐responsive interactors of the V‐ATPase V1A subunit (encoded by ATP6V1A ). We found that mTORC1 inhibition disrupts the R2TP‐V1A interaction, promoting the relocation of the V1 domain to lysosomes and its assembly with the Vo domain to form active proton pumps. Functionally, knockdown of RPAP3 or PIH1D1 enhanced autophagic flux, increased lysosomal proteolytic activity, and promoted the clearance of soluble α‐synuclein in a cellular model of Parkinson's disease (PD). Our study reveals the R2TP complex as a critical molecular switch that couples mTORC1 signaling to V‐ATPase assembly and lysosomal function, thereby identifying a new pathway for regulating lysosomal catabolism with significant therapeutic potential for neurodegenerative disorders.
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with multi-system involvement, and its pathogenesis is complex, involving abnormalities of multiple immune cells and molecules. In recent years, the role of the transcription factor Forkhead Box P3 (FOXP3) in SLE has attracted much attention. FOXP3, a crucial indicator of regulatory T cells (Tregs), is essential for maintaining immune tolerance and suppressing excessive immune responses. This review systematically elucidates the multi-tiered regulatory networks that control FOXP3 expression at the transcriptional, epigenetic, and post-translational levels. It further examines the specific phenotypic alterations and molecular mechanisms responsible for the dysregulation of Treg quantity, function, and stability within the SLE milieu, including factors such as interleukin (IL)-2 deficiency, cytokine storms, and epigenetic abnormalities. Building upon this foundation, the article explores a range of emerging therapeutic strategies targeting FOXP3 and Tregs as central elements, highlighting recent advances and clinical translation prospects in low-dose IL-2 therapy, adoptive Treg cell transfer, and epigenetic drug interventions. Ultimately, we propose that the precise modulation and enhancement of Treg function to restore stable immune tolerance in SLE patients constitutes a novel therapeutic paradigm, transitioning from broad immunosuppression toward targeted immune modulation. This strategy holds significant promise for fundamentally improving the therapeutic landscape of this complex autoimmune disorder.
The Warburg effect-induced lactate production in T-cell acute lymphoblastic leukemia (T-ALL) cell proliferation is well established, however, the role of lactate-mediated protein lactylation in this process remains poorly understood. In this study, we demonstrated that inhibiting lactate levels through the lactate dehydrogenase A (LDHA) inhibitor significantly reduced both cell proliferation and protein lactylation levels in T-ALL cells. Lactate deficiency led to a marked decrease in protein lactylation, accompanied by impaired cell proliferation. Meanwhile, lactate deficiency also induced the S‑phase cell cycle arrest and reduced DNA synthesis, which collectively impaired cell proliferation. Mechanistically, we observed that the decreased expression of lactylation in histone H3 at lysine 18 (H3K18lac) reduced the enrichment of this mark on the promoter region of neurotrophic receptor tyrosine kinase 3 (NTRK3), which supported the cell proliferation of T-ALL cells. Moreover, the overexpression of NTRK3 rescued the lactate deficiency-induced proliferation inhibition of T-ALL cells. Furthermore, exogenous lactate supplementation dramatically restored the decreased cell proliferation in T-ALL cells and restored H3K18lac levels. Our findings reveal a novel role of lactate-mediated protein lactylation in regulating T-ALL cell proliferation.
