SIRT5, a mitochondrial sirtuin, is a NAD-dependent protein lysine desuccinylase and demalonylase [6]. It plays a crucial role in regulating various metabolic pathways, including amino acid degradation, the tricarboxylic acid cycle, and fatty acid metabolism [5]. Protein lysine succinylation regulated by SIRT5 impacts the function of enzymes involved in these metabolic processes, and SIRT5 is also present in extramitochondrial locations [5].

In different disease-related studies, genetic models have provided insights. In pancreatic ductal adenocarcinoma (PDAC), Sirt5 knockout in mouse models promoted acinar-to-ductal metaplasia, precursor lesions, and pancreatic tumorigenesis, indicating SIRT5 as a tumor suppressor in PDAC [4]. In hepatocellular carcinoma (HCC), Sirt5 deficiency in mice increased bile acid production, creating an immunosuppressive tumor microenvironment that favored tumor-initiating cells [1]. In intervertebral disc degeneration (IDD), Sirt5 knockout mice showed more severe IDD phenotypes compared to wild-type mice after lumbar spine instability surgery, with SIRT5 protecting against IDD by regulating mitochondrial homeostasis [2]. In diabetic cardiomyopathy, ablation of Sirt5 in mice exacerbated cardiac dysfunction, hypertrophy, and lipotoxicity, while forced expression improved these conditions, with SIRT5 acting through CPT2 de-succinylation to improve fatty acid metabolism [3].

In conclusion, SIRT5 is a key regulator of metabolic pathways through its desuccinylase activity. Gene knockout mouse models have revealed its significance in diseases such as PDAC, HCC, IDD, and diabetic cardiomyopathy. Understanding SIRT5's functions can potentially provide new therapeutic strategies for these diseases.