Department of Health Science, University of Piemonte Orientale, Novara 28100, Italy.
Division of Experimental Oncology/Unit of Urology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy.
Clin Sci (Lond). 2021 Jan 15;135(1):161-166. doi: 10.1042/CS20201091.
Ischemia-reperfusion injury (IRI) consequent to major liver surgery is a still unmet clinical problem. The activation of endogenous systems of hepatoprotection can prevent the damaging effects of ischemia-reperfusion (IR) as shown by the phenomenon known as 'ischemic preconditioning'. The identification of endogenous signal mediators of hepatoprotection is of main interest since they could be targeted in future therapeutic interventions. Qiu et al. recently reported in Clin. Sci. (Lond.) (2020) 134(17), 2279-2294, the discovery of a novel protective molecule against hepatic IR damage: dual-specificity phosphatase 12 (DUSP12). IR significantly decreased DUSP12 expression in liver whereas DUSP12 overexpression in hepatocytes protected IRI and DUSP12 deletion in DUSP12 KO mice exacerbated IRI. The protective effects of DUSP12 depended on apoptosis signal-regulating kinase 1 (ASK1) and acted through the inhibition of the ASK1-dependent kinases c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). These results enlighten DUSP12 as a novel intermediate negative regulator of the pro-inflammatory and pro-apoptotic ASK1/JNK-p38 MAPK pathway activated during hepatic IR and identify DUSP12 as potential therapeutic target for IRI.
缺血再灌注损伤（IRI）是肝大手术后尚未解决的临床问题。内源性肝保护系统的激活可以预防缺血再灌注（IR）的损伤作用，这一现象被称为“缺血预处理”。内源性肝保护信号介质的鉴定具有重要意义，因为它们可能成为未来治疗干预的靶点。邱等人最近在《临床科学杂志》（Lond.）（2020 年）134（17），2279-2294 上报道，发现了一种新的抗肝 IR 损伤的保护分子：双特异性磷酸酶 12（DUSP12）。IR 显著降低了肝组织中 DUSP12 的表达，而肝细胞中 DUSP12 的过表达可保护 IRI，DUSP12 KO 小鼠中 DUSP12 的缺失则加剧了 IRI。DUSP12 的保护作用依赖于凋亡信号调节激酶 1（ASK1），并通过抑制 ASK1 依赖性激酶 c-Jun N 末端激酶（JNK）和丝裂原活化蛋白激酶（MAPK）p38 的活性起作用。这些结果表明 DUSP12 是肝 IR 过程中激活的促炎和促凋亡 ASK1/JNK-p38 MAPK 通路的新型中间负调控因子，并确定 DUSP12 可能成为 IRI 的治疗靶点。
