Author: Ashrafizadeh, Milad ; Chen, Qingling ; Li, Bin ; Guo, Jun ; Guo, Chuxian ; Li, Fengjuan ; Wu, Liangxiu ; Li, Lishan ; Lan, Xianwu ; Wu, Liangyan ; Sethi, Gautam ; Li, Lanlan ; Ye, Haowen

Dysfunction of keratinocytes affects diabetic wound healing, but underlying mechanisms have not been understood. This study examines crotonylation's role in ferroptosis and autophagy in keratinocytes, particularly regarding ACSL4, using STZ-induced diabetic rats and high glucose-exposed keratinocytes to assess these processes. The ACSL4 knockdown was achieved using adenovirus in wounds to examine the impact of ferroptosis modulation on healing diabetic wounds. MB-3 was utilized to block the H3K27 crotonylation (H3K27cr) in order to clarify the regulatory function of crotonylation in both autophagy and ferroptosis. In STZ-induced diabetic skin and high glucose-exposed keratinocytes, ferroptosis mediated by ACSL4 and suppression of autophagic flux were demonstrated. Moreover, the downregulation of ACSL4 triggered ferroptosis in adjacent wounds of diabetic rats and improved wound healing. The degradation of ACSL4 may be observed via the autophagy-lysosome pathway in keratinocytes. Downregulation of SQSTM1 in diabetic keratinocytes leads to autophagy inhibition and modulates the protein level of ACSL4. Mechanistically, total crotonylation levels and H3K27cr were remarkably elevated in the skin and keratinocytes of diabetic rats; blocking high glucose-induced H3K27cr with MB-3 can enhance SQSTM1 transcription and expression while promoting autophagy and reducing ACSL4-induced ferroptosis in keratinocytes. Therefore, H3K27cr influences autophagy by adjusting SQSTM1 to facilitate ACSL4-triggered ferroptosis in diabetic keratinocytes. This study clarifies the relationships between acylation modifications, autophagy, and ferroptosis, while also offering mechanistic insights and potential therapeutic targets for issues associated with diabetic wound healing.

01 Feb 2025·Gastroenterology

The Moonlighting Function of Glutaminase 2 Promotes Immune Evasion of Pancreatic Ductal Adenocarcinoma by Tubulin Tyrosine Ligase-like 1-Mediated Yes1 Associated Transcriptional Regulator Glutamylation

Article

Author: Fu, Hong ; Mao, Zhengwei ; Zheng, Xiaofeng ; Zhu, Shimao ; Hu, Xun ; Chao, Ming ; Zhang, Sitong ; Sun, Zhongquan ; Fu, Haotian ; Xiang, Zheng ; Ding, Yuan ; Wang, Weilin ; Bi, Yanli ; Chen, Xiao

BACKGROUND & AIMSElevated programmed cell death-ligand 1 (PD-L1) expression in tumor cells facilitates immune evasion. However, the mechanism via which PD-L1 expression is regulated in pancreatic ductal adenocarcinoma (PDAC) cells remains inadequately elucidated.METHODSImmunoprecipitation, pull-down assays, and mass spectrometry were used to identify glutaminase 2 (GLS2) and yes1 associated transcriptional regulator (YAP1) binding proteins and modification sites. Immunoblotting, immunofluorescence, chromatin immunoprecipitation, and luciferase reporter assays were used to analyze YAP1 activation. Protein expression levels were assessed using immunoblotting, immunoprecipitation, immunofluorescence, and immunohistochemistry. RNA expression levels were analyzed using real-time quantitative polymerase chain reaction.RESULTSHypoxia-induced general control nondepressible 5 (GCN5)-mediated acetylation of GLS2 at K151, which enhanced GLS2 interaction with YAP1. Subsequently, tubulin tyrosine ligase-like 1 mediated YAP1 glutamylation at E100 and promoted its nuclear translocation and the activation-dependent transcriptional up-regulation of PD-L1 expression. The expression of GLS2-K151R or YAP1-E100A mutants in PDAC cells blocked hypoxia-induced PD-L1 expression and enhanced CD4⁺ and CD8⁺ T-cell activation and tumor infiltration, thereby suppressing PDAC tumor growth. Simultaneous administration of MB-3, a GCN5 inhibitor, and an anti-programmed cell death 1 (PD-1) antibody abolished tumor immune evasion, boosting the anti-tumor efficacy of immune checkpoint blockade. Furthermore, GLS2-K151 acetylation and YAP1 E100 glutamylation levels correlated positively with PD-L1 expression and poor prognosis in PDAC patients.CONCLUSIONSThe present study revealed a novel mechanism by which hypoxia up-regulates PD-L1 expression and highlighted the involvement of GLS2 in noncanonical metabolic pathways involved in tumor immune evasion, with implications for PDAC treatment.

01 Jun 2023·MedComm

Targeting KAT2A inhibits inflammatory macrophage activation and rheumatoid arthritis through epigenetic and metabolic reprogramming

Article

Author: Jiang, Yuyu ; Ding, Yingying ; Zhang, Yunkai ; Gao, Ying ; Liu, Xingguang ; Zhan, Zhenzhen ; Chen, Huiying

AbstractEpigenetic regulation of inflammatory macrophages governs inflammation initiation and resolution in the pathogenesis of rheumatoid arthritis (RA). Nevertheless, the mechanisms underlying macrophage‐mediated arthritis injuries remain largely obscure. Here, we found that increased expression of lysine acetyltransferase 2A (KAT2A) in synovial tissues was closely correlated with inflammatory joint immunopathology in both RA patients and experimental arthritis mice. Administration of MB‐3, the KAT2A‐specific chemical inhibitor, significantly ameliorated the synovitis and bone destruction in collagen‐induced arthritis model. Both pharmacological inhibition and siRNA silencing of KAT2A, not only suppressed innate stimuli‐triggered proinflammatory gene (such as Il1b and Nlrp3) transcription but also impaired NLR family pyrin domain containing 3 (NLRP3) inflammasome activation in vivo and in vitro. Mechanistically, KAT2A facilitated macrophage glycolysis reprogramming through suppressing nuclear factor‐erythroid 2‐related factor 2 (NRF2) activity as well as downstream antioxidant molecules, which supported histone 3 lysine 9 acetylation (H3K9ac) and limited NRF2‐mediated transcriptional repression of proinflammatory genes. Our study proves that acetyltransferase KAT2A licenses metabolic and epigenetic reprogramming for NLRP3 inflammasome activation in inflammatory macrophages, thereby targeting KAT2A represents a potential therapeutic approach for patients suffering from RA and relevant inflammatory diseases.

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Indication	Highest Phase	Country/Location	Organization	Date
Hemorrhagic Fever, Ebola	Preclinical	United States	Mapp Biopharmaceutical, Inc.	15 Oct 2012

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