Mdh2, or mitochondrial malate dehydrogenase 2, is a key enzyme in the tricarboxylic acid (TCA) cycle. The TCA cycle is crucial for energy production through oxidative phosphorylation and is involved in various anabolic processes [1,2,3,4,5,8]. Mdh2's function in the TCA cycle is essential for maintaining normal cellular metabolism and energy homeostasis, and its study using genetic models can provide insights into its role in different biological contexts.

MDH2 has been associated with multiple disease conditions. In ovarian cancer, palmitoylation of MDH2 at cysteine 138 by ZDHHC18 activates mitochondrial respiration and accelerates cancer growth, and MDH2 silencing represses mitochondrial respiration and cancer cell proliferation both in vitro and in vivo [1]. In clear cell renal cell carcinoma (ccRCC), knocking out MDH2 enhances ccRCC cell proliferation while promoting ferroptosis sensitivity, and MDH2 regulates FSP1 ubiquitination, affecting ccRCC sensitivity to ferroptosis [4]. In hepatocellular carcinoma (HCC), MDH2 deficiency inhibits HCC cell growth and enhances ferroptosis sensitivity, and MDH2 stabilizes GPX4 to evade ferroptosis [5]. In gastrointestinal stromal tumors, USP5 promotes ripretinib resistance by deubiquitinating MDH2, and ZDHHC18 can palmitoylate MDH2 to increase its stability [6]. In ischemic stroke, microglial lnc-U90926 binds to MDH2, regulating CXCL2 mRNA decay and neutrophil infiltration [7].

In conclusion, Mdh2 plays a vital role in regulating cellular metabolism, especially through its function in the TCA cycle. Studies using knockout or knockdown models have revealed its significant impact on cancer development, including ovarian, renal, and liver cancers, as well as its role in drug resistance in gastrointestinal stromal tumors and in ischemic stroke. These findings highlight Mdh2 as a potential therapeutic target in these disease areas.