Challenges in Pharmacological Intervention in Perilipins (PLINs) to Modulate Lipid Droplet Dynamics in Obesity and Cancer

SIMPLE SUMMARY: This review highlights the importance of perilipins in lipid metabolism and their potential as therapeutic targets for lipid-associated diseases like cancer and obesity. Perilipins are proteins found in lipid droplets that regulate lipase activity and play a crucial role in maintaining the balance between lipid synthesis and breakdown. Modulating perilipins could improve existing treatments or offer new therapeutic opportunities for addressing these diseases. ABSTRACT: Perilipins (PLINs) are the most abundant proteins in lipid droplets (LD). These LD-associated proteins are responsible for upgrading LD from inert lipid storage structures to fully functional organelles, fundamentally integrated in the lipid metabolism. There are five distinct perilipins (PLIN1–5), each with specific expression patterns and metabolic activation, but all capable of regulating the activity of lipases on LD. This plurality creates a complex orchestrated mechanism that is directly related to the healthy balance between lipogenesis and lipolysis. Given the essential role of PLINs in the modulation of the lipid metabolism, these proteins can become interesting targets for the treatment of lipid-associated diseases. Since reprogrammed lipid metabolism is a recognized cancer hallmark, and obesity is a known risk factor for cancer and other comorbidities, the modulation of PLINs could either improve existing treatments or create new opportunities for the treatment of these diseases. Even though PLINs have not been, so far, directly considered for pharmacological interventions, there are many established drugs that can modulate PLINs activity. Therefore, the aim of this study is to assess the involvement of PLINs in diseases related to lipid metabolism dysregulation and whether PLINs can be viewed as potential therapeutic targets for cancer and obesity.