Abhd16a, a member of the α/β hydrolase domain-containing (ABHD) protein family, is expressed in various animal cells. It has acylglycerol lipase and phosphatidylserine lipase activities. Located in the main histocompatibility complex (MHC) III gene cluster, it may participate in immunomodulation [1]. It is also involved in lipid metabolism, generating lysophosphatidylserine (lyso-PS), a signaling lipid important in the mammalian central nervous system [2,5,6,7].

In gene-related diseases, loss-of-function of Abhd16a due to bi-allelic deleterious variants leads to a complicated form of hereditary spastic paraplegia (HSP). Affected individuals show global developmental delay/intellectual disability, progressive spasticity, and corpus callosum and white matter anomalies [2]. In vitro, Abhd16a loss of function in patient-derived fibroblasts reduces certain long-chain lyso-PS species and increases multiple phosphatidylserine species [3]. In cancer, in the tumor microenvironment, genetic deletion of Abhd16a expression in tumors enhances the antitumor activity of type 1 innate lymphoid cells (ILC1s), as LysoPS, whose synthesis is regulated by Abhd16a, can inhibit ILC1 activation [4]. In gastric cancer, miR-4646-5p, a product of Abhd16a intron 3, can regulate Abhd16a expression, and Abhd16a-mediated lyso-PS accumulation promotes cancer metastasis [5].

In conclusion, Abhd16a is crucial for lipid metabolism, especially in the synthesis of lyso-PS. Its dysfunction is implicated in hereditary spastic paraplegia and cancer-related immune regulation. Studies using loss-of-function models, such as in patients with genetic variants in Abhd16a, have provided insights into its role in these disease conditions, highlighting its potential as a therapeutic target for related disorders.