Ho-Geun Yoon

Idiopathic pulmonary fibrosis (IPF) is a fatal and progressive respiratory disease characterized by aberrant epithelial remodeling, excessive extracellular matrix (ECM) deposition, and fibroblast activation. Although LKB1-AMPK signaling axis is known to suppress epithelial-to-mesenchymal transition (EMT) and lung fibrosis, the upstream regulatory mechanisms governing this pathway remain unclear. General control non-depressible 5 (GCN5) is a lysine acetyltransferase that modulates protein function and cellular pathways via acetylation, but its contribution to lung fibrosis has not been investigated. To investigate the role of GCN5 in pulmonary fibrosis, we analyzed publicly available transcriptomic datasets from IPF patients. GCN5 expression was validated in lung tissues from IPF patients and mouse fibrosis models (lung-specific TGF-β₁ transgenic and bleomycin-treated mice) using immunohistochemistry. Protein-protein interactions between GCN5 and LKB1 were assessed by co-immunofluorescence in mouse tissues and in vitro translation followed by immunoprecipitation. LKB1 acetylation sites were identified using in silico docking system and functionally validated by site-directed mutagenesis. GCN5 knockdown and overexpression were performed in lung epithelial cells to examine downstream signaling. To evaluate therapeutic potential, GCN5-expressing adenovirus was delivered intratracheally to bleomycin-treated mice. Here, we revealed a significantly reduced expression of GCN5 in lung tissues from both patients with IPF and lung fibrosis mouse models. Notably, GCN5 directly bound to liver kinase B1 (LKB1), a master regulator of AMP-activated protein kinase (AMPK), and acetylated LKB1 lysine residues at its C-terminal region. In particular, GCN5-mediated LKB1 acetylation at lysine 431 (K431) enhanced LKB1 kinase activity. GCN5 knockdown in lung epithelial cells reduced LKB1 acetylation at K431, leading to decreased AMPK phosphorylation and subsequent promotion of EMT. Conversely, GCN5 overexpression reversed transforming growth factor-beta–induced profibrotic phenotype. Furthermore, adenovirus-mediated overexpression of GCN5 alleviated fibrosis in bleomycin-treated mice. Our findings identify GCN5 as a novel upstream regulator of the LKB1–AMPK signaling in lung epithelial cells. GCN5 deficiency in fibrotic conditions reduces LKB1 acetylation and disrupts epithelial homeostasis, facilitating EMT and fibrosis progression. Restoring GCN5 expression rescues this signaling axis and mitigates fibrosis, highlighting its potential as a therapeutic target of IPF. The online version contains supplementary material available at 10.1186/s12964-026-02757-8.

Here we aim to elucidate the role of the p300/CBP-associated factor (PCAF) in pathological cardiac remodeling. Specifically, we explore how PCAF-mediated acetylation of calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) influences AMPK signaling, thereby regulating cardiac hypertrophy and dysfunction under pathological stress. A genetically engineered PCAF-knockout (KO) mouse model was generated using the CRISPR–Cas9 system to evaluate the effect of PCAF deficiency on cardiac remodeling induced by isoproterenol infusion and transverse aortic constriction (TAC). PCAF deficiency significantly aggravated cardiac enlargement with features of eccentric hypertrophy, as demonstrated by histological analysis and echocardiography. To determine these phenotypes were cardiomyocyte specific, we generated a cardiomyocyte-specific conditional KO model, which also showed a dilated cardiomyopathy-like phenotype similar to that of the global-KO mice. Transcriptomic analysis of TAC-operated hearts from wild-type and KO mice revealed enrichment of pathways related to mitochondrial function and energy homeostasis. Mechanistically, PCAF directly acetylated CAMKK2, promoting its activation and the subsequent phosphorylation of AMP-activated protein kinase α (AMPKα) at Thr172, a critical step in maintaining metabolic balance under stresses. These signaling alterations were also observed in the hearts of PCAF-KO hearts subjected to isoproterenol administration or TAC. Pharmacological activation of PCAF with SPV106 effectively attenuated TAC-induced cardiac remodeling, preserving cardiac structure and function. Collectively, these findings identify PCAF as a pivotal regulator of pathological cardiac remodeling through modulation of the CAMKK2–AMPK signaling axis. Loss of PCAF exacerbates stress-induced cardiac hypertrophy and dysfunction, highlighting its potential as a therapeutic target to preserve cardiac function and counteract stress-induced remodeling.

Hepatic stellate cell (HSC) activation is a central mechanism in liver fibrosis, with histone acetyltransferase p300 acting as a pivotal transcriptional cofactor. To define upstream regulators of p300 stability during HSC activation, we performed a deubiquitinase inhibitor screen in activated HSCs and identified ubiquitin carboxyl‐terminal hydrolase 2 (USP2) as a p300 deubiquitinase. Single‐cell RNA sequencing of fibrotic human liver tissues revealed USP2 as the most specifically expressed USP family member in stromal populations, including HSCs, with marked upregulation in chronic liver disease and advanced metabolic dysfunction‐associated steatotic liver disease (MASLD). Moreover, we demonstrated that USP2 stabilizes p300 and promotes HSC activation, whereas USP2 knockdown or pharmacological inhibition suppresses p300 accumulation and fibrogenic responses. These findings identify USP2 as a key regulator of p300 stability and HSC activation in liver fibrosis. Impact statement: Our study identifies USP2 as a novel regulator of p300 stability and hepatic stellate cell activation, revealing a previously unrecognized mechanism driving liver fibrosis. These findings provide new insight into fibrogenesis and highlight USP2 as a potential therapeutic target, impacting both fundamental biology and translational fibrosis research.

Renal fibrosis is a consequence of chronic kidney disease, which is estimated to affect 10–14% of the global population. The molecular mechanisms in the pathogenesis of renal fibrosis are still unclear, and there is a lack of effective therapies. Here we identified decreased levels of p300/CBP-associated factor (PCAF) in kidney tissues with fibrosis and demonstrated that PCAF-specific knockout in proximal tubular cells accelerates renal fibrosis in both unilateral ureteral obstruction surgery and folic acid-induced models. Conversely, overexpressing PCAF in the kidney using adenovirus mitigated unilateral ureteral obstruction-induced renal fibrosis. Importantly, PCAF inhibits the epithelial-to-mesenchymal transition of proximal tubular cells by transcriptionally activating adherens junction genes. Moreover, we observed that TGF-β signaling induces lysosomal degradation of PCAF, suggesting that PCAF reduction is affected in the fibrotic milieu. These findings confirm that PCAF is a negative regulator of renal fibrosis and suggest that it could serve as a novel therapeutic target for patients with chronic kidney disease.

Chronic kidney disease (CKD) has a high prevalence worldwide and is typically accompanied by severe fibrosis. However, the exact pathogenesis of renal fibrosis and effective treatments have yet to be identified. In this study, we found that expression of the histone-acetyltransferase p300 was increased in focal segmental glomerulosclerosis patients and several distinct mouse models of renal fibrosis. Moreover, we showed that the AKT-mediated phosphorylation of Ser-1834 of p300 increased the stability of p300 upon renal fibrosis induction, and conversely, PPM1K specifically dephosphorylated p300 at Ser-1834, resulting in a significant reduction in p300 stability and renal fibrosis. Interestingly, increased p300 in proximal tubular cells (PTCs) promoted renal fibrosis development by mediating the endothelial to mesenchymal transition (EndMT) via upregulation of the mesenchymal-transition-related secreted proteins POSTN, FSTL1, and FSCN1. Both EndMT and renal fibrosis were significantly diminished by either PTC-specific deletion of p300 gene or selective inhibitors of p300. Collectively, our results demonstrate the role of p300 in the development of renal fibrosis, and suggest that p300 is a promising target for treatment of advanced CKD.

Hyunsik Kim, Subhin Jang, Soo Yeon Lee, Jae-Hwan Kwon, Seunghee Byun, Jung-Yoon Yoo, Sungryul Yu, Soo-Yeon Park & Ho-Geun Yoon. BMB Reports -0001;0:. https://doi.org/10.5483/BMBRep.2024-0027