https://ir.ymlib.yonsei.ac.kr/handle/22282913/168760 2026-04-13T16:56:49Z https://ir.ymlib.yonsei.ac.kr/handle/22282913/211500 Title: Deubiquitinase USP2 promotes hepatic stellate cell activation via p300 stabilization Authors: Byun, Seunghee; Kim, Hyunsik; Lee, Sun-Ho; Kwon, Jae-Hwan; Kim, Hyunseung; Yoo, Jung-Yoon; Park, Soo-Yeon; Yoon, Ho-Geun Abstract: 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. 2026-02-01T00:00:00Z https://ir.ymlib.yonsei.ac.kr/handle/22282913/210461 Title: Limitations of Ferroptosis Inhibitors on the Doxorubicin-Induced Cardiotoxicity Authors: Cha, Yun-Ji; Jeon, Sae-Bom; Lee, Chan Joo; Kim, Hyeong-Jin; Lee, Sun-Ho; Kim, Hyoeun; Park, So Hee; Chen, Elaine Zhelan; Kim, Jong Woo; Park, Sahng Wook; Kwon, Chulan; Joung, Boyoung; Lee, Eun-Woo; Lee, Seunghyun Abstract: Doxorubicin is an anthracycline anticancer drug commonly used to treat lymphoma and breast cancer. Its major side effect is cardiotoxicity, which occurs by damaging cardiomyocytes. The mechanisms of doxorubicin-induced cardiotoxicity remain unclear; however, recent studies suggest that ferroptosis, an iron-dependent form of lipid peroxidation-mediated cell death, may play a key role. In this study, we investigated the role of ferroptosis in doxorubicin-induced cardiotoxicity using ferroptosis-specific inhibitors (ferrostatin-1 and liproxstatin-1). In both H9c2 cardiomyocyte cell lines and human induced pluripotent stem cell-derived cardiomyocytes, ferrostatin-1 and liproxstatin-1 rescued cell death induced by RSL3, a ferroptosis inducer, but failed to prevent doxorubicin-induced cell death. Additionally, the ferroptosis inhibitors did not restore the electrophysiological function of cardiomyocytes, measured using a multi-electrode array system, and instead slightly accelerated cardiomyocyte beating. Finally, doxorubicin-injected mice treated with ferroptosis inhibitors exhibited significantly reduced survival and increased levels of N-terminal pro B-type natriuretic peptide, a biomarker of heart failure. These findings suggest that inhibiting ferroptosis alone is insufficient to mitigate doxorubicin-induced cardiotoxicity. 2026-01-01T00:00:00Z https://ir.ymlib.yonsei.ac.kr/handle/22282913/211368 Title: p300-Dependent modulation in regulatory T cells plays a crucial role in allergic asthma Authors: Kim, Eun Gyul; Kim, Mi Na; Park, Soo-Yeon; Park, Chang Hyun; Cho, Joo Yeon; Ko, Byung Chan; Park, Sung Woo; Kim, Kyung Won; Yoon, Ho-Geun; Sohn, Myung Hyun Abstract: Rationale Asthma is a chronic inflammatory airway disease, affected by epigenetic modifications. E1A binding protein p300 (p300) is a pivotal histone acetyltransferase that regulates the transcription of diverse genes.Objectives We investigated the role of p300 in regulating immune responses during allergic asthma.Methods An allergen-induced asthma model was established in mice with systemic p300 deletion and regulatory T cell (Treg)-specific p300 deletion. Histone acetyltransferase activity and p300 expression were evaluated in asthma-induced mice and biopsy samples from patients with asthma. Next, immune responses of T helper 2 (Th2) cells and Tregs were investigated. Additionally, chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq) were conducted using the sorted Tregs. Functional studies of guanylate binding protein 5 (GBP5) in Tregs were confirmed through in vitro inhibition and overexpression tests.Measurements and Main Results Histone acetyltransferase activity and p300 levels were elevated in mice with asthma. p300 expression was also higher in patients with asthma than in control subjects. Mice with systemic p300 deletion had elevated type 2 immune responses and decreased Treg population and functions. Furthermore, p300 deletion reduced the suppression ability and differentiation potential of Tregs. Allergic inflammation was also exacerbated in mice with Treg-specific p300 deletion. ChIP-seq and RNA-seq revealed GBP5 as a primary target gene of p300 in Tregs. GBP5 overexpression ameliorated the reduction in Treg proliferation caused by p300 depletion.Conclusions p300 plays a protective role in allergic asthma by enhancing Treg function, partly through GBP5-mediated regulation, thereby suppressing Th2-driven airway inflammation. 2026-01-01T00:00:00Z https://ir.ymlib.yonsei.ac.kr/handle/22282913/210149 Title: Pharmacological inhibition of Ubiquitin-Specific Peptidase 10 (USP10) with spautin-1 attenuates adipogenesis through CCAAT/Enhancer-Binding Protein Beta (C/EBPβ) destabilization Authors: Erdenebileg, Zolzaya; Simamora, Desy Damayanti; Park, Joong-Kwon; Nogueira, Rosana; Kim, Young Bin; Choi, Jeong-Yun; Kang, Hyeon-Gu; Choi, Hack Sun; Baek, Jung-Hwan; Chun, Kyung-Hee Abstract: The pharmacological control of lipid accumulation in white adipose tissue (WAT) is a key area of focus in obesity research, yet the role of deubiquitination in adipocyte lipid storage remains underexplored. We found that spautin-1, an inhibitor of the deubiquitinases ubiquitin-specific peptidase 10 (USP10) and 13 (USP13), suppressed lipid accumulation during adipogenesis. Therefore, we investigated whether blocking deubiquitination restricts adipogenesis and acts as the underlying mechanism. Mining public datasets revealed that USP10 expression is substantially increased in the adipose tissue (AT) from individuals with obesity. Moreover, USP10 exhibited a depot-specific expression pattern, with higher levels in visceral AT than in subcutaneous AT, whereas no such difference was observed for USP13. Consistently, in high-fat diet-fed mice, USP10 was markedly upregulated in gonadal WAT, whereas USP13 was undetectable. Genetic ablation of USP10 phenocopied spautin-1 treatment by reducing the expression of the components of the peroxisome proliferator-activated receptor gamma (PPAR gamma)/CCAAT/enhancer-binding protein alpha (C/EBP alpha) axis, while USP13 knockdown induced minimal effects, thus implicating USP10 as the principal mediator. Mechanistically, USP10 directly interacted with C/EBP beta and stabilized it via deubiquitination. However, spautin-1 or USP10 knockdown enhanced C/EBP beta ubiquitination and proteolysis, thereby impairing the adipogenic commitment. The overexpression of wild-type USP10, but not its catalytically inactive mutant, rescued C/EBP beta stability, thus confirming the requirement for its enzymatic activity. The administration of spautin-1 to high-fat diet-fed mice mitigated body weight gain and reduced adipose tissue mass in vivo. Notably, spautin-1 selectively suppressed USP10 and C/EBP beta in gonadal WAT without affecting the liver, which highlights the tissue-specific pharmacodynamics. Collectively, these findings define the USP10-C/EBP beta axis as a key regulator of adipogenesis and position spautin-1 as a mechanistically grounded anti-obesity candidate that warrants translational evaluation. 2025-12-01T00:00:00Z