Hepatocellular SETDB1 Regulates Hepatic Ischemia-Reperfusion Injury through Targeting Lysine Methylation of ASK1 Signal

Abstract

Background: Hepatic ischemia-reperfusion injury (HIRI) stands as an unavoidable complication arising from liver surgery, profoundly intertwined with its prognosis. The role of lysine methyltransferase SET domain bifurcated 1 (SETDB1) in HIRI remains elusive, despite its confirmation as a potential therapeutic target for diverse diseases. Here, we investigated the mechanism by which SETDB1 regulated HIRI. Methods: RNA sequencing data were used to identify the expression and potential targets of SETDB1 through bioinformatics analysis. To elucidate the impact of SETDB1 on HIRI, both an in vivo model of HIRI in mice and an in vitro model of hepatocyte hypoxia/reoxygenation were established. Biochemical and histological analyses were used to investigate the influence of SETDB1 on liver damage mediated by HIRI. Chromatin immunoprecipitation and coimmunoprecipitation were implemented to explore the in-depth mechanism of SETDB1 regulating HIRI. Results: We confirmed that hepatocellular SETDB1 was up-regulated during HIRI and had a close correlation with HIRI-related inflammation and apoptosis. Moreover, inhibition of SETDB1 could mitigate HIRI-induced liver damage, inflammation, and apoptosis. Through our comprehensive mechanistic investigation, we revealed that SETDB1 interacts with apoptosis-signal-regulating kinase 1 (ASK1) and facilitates the methylation of its lysine residues. Inhibition of SETDB1 resulted in reduced phosphorylation of ASK1, leading to a marked suppression of downstream c-Jun N-terminal kinase (JNK)/p38 signaling pathway activation. The therapeutic effect on inflammation and apoptosis achieved through SETDB1 inhibition was nullified by the restoration of JNK/p38 signaling activation through ASK1 overexpression. Conclusions: The findings from our study indicate that SETDB1 mediates lysine methylation of ASK1 and modulates the activation of the ASK1–JNK/p38 pathway, thus involved in HIRI-induced inflammation and apoptosis. These results suggest that SETDB1 holds promise as a potential therapeutic target for mitigating HIRI.

Engineering tumor-oxygenated nanomaterials: advancing photodynamic therapy for cancer treatment

“…Carrier nutrients, such as nanoparticles or liposomes, can be utilized to transport O 2 to tumor sites ( Zhang et al, 2018 ; Li et al, 2019 ). These carriers have the ability to encapsulate and protect O 2 molecules, ensuring their safe delivery to the TME ( Song et al, 2017 ; Xia et al, 2023 ). Additionally, carrier nutrients can be engineered to specifically target tumor cells, further enhancing their therapeutic potential.…”

“…Another strategy for tumor vasculature normalization involves the use of physical interventions, such as radiation therapy or focused ultrasound (Chen K. T. et al, 2023;Leong et al, 2023). These techniques can selectively damage the abnormal blood vessels, leading to their regression and subsequent normalization.…”

“…Mitochondrial respiration is a crucial process that enables cells to generate energy in the form of adenosine triphosphate (ATP). Cancer cells heavily rely on this energy production pathway to sustain their rapid growth and proliferation (Wang Q. et al, 2023;Zhao et al, 2023). Therefore, by selectively inhibiting mitochondrial respiration, it is possible to selectively target cancer cells while sparing healthy cells.…”

“…Overall, the use of catalysis to generate O 2 within tumor tissues holds great potential in improving the effectiveness of cancer treatment (Zetrini et al, 2023). By addressing the hypoxic microenvironment, this approach can enhance the outcomes of radiation therapy, chemotherapy, and immunotherapy, ultimately leading to better patient outcomes (Chen Z. et al, 2023). Further research and development in this field are necessary to optimize the Frontiers in Bioengineering and Biotechnology frontiersin.org catalytic agents and their delivery methods, but the future looks promising for this innovative approach to cancer treatment (Petrova et al, 2018).…”