*Review* **Natural Products and Small Molecules Targeting Cellular Ceramide Metabolism to Enhance Apoptosis in Cancer Cells**

**Farjana Afrin 1, Sameena Mateen 1, Jordan Oman 1, James C. K. Lai 1, Jared J. Barrott <sup>2</sup> and Srinath Pashikanti 1,\***


**Simple Summary:** Ceramide and associated enzymes play a substantial role in cell function such as in cell proliferation, differentiation, and apoptosis processes. Knowing the enzymatic pathway and targeting particular enzymes from that pathway can lead to a very successful therapeutic outcome. As such, this review is focused on the elaboration of the natural products and small inhibitor molecules that can target important enzymes such as ceramidase and ceramide synthase that participate in the central lipid ceramide pathway, as well as the outcome when those pathways are disturbed during disease progression. In addition, this paper also discusses cancer that is associated with the imbalance of ceramide enzymes.

**Abstract:** Molecular targeting strategies have been used for years in order to control cancer progression and are often based on targeting various enzymes involved in metabolic pathways. Keeping this in mind, it is essential to determine the role of each enzyme in a particular metabolic pathway. In this review, we provide in-depth information on various enzymes such as ceramidase, sphingosine kinase, sphingomyelin synthase, dihydroceramide desaturase, and ceramide synthase which are associated with various types of cancers. We also discuss the physicochemical properties of wellstudied inhibitors with natural product origins and their related structures in terms of these enzymes. Targeting ceramide metabolism exhibited promising mono- and combination therapies at preclinical stages in preventing cancer progression and cemented the significance of sphingolipid metabolism in cancer treatments. Targeting ceramide-metabolizing enzymes will help medicinal chemists design potent and selective small molecules for treating cancer progression at various levels.

**Keywords:** natural products and related small molecules; sphingolipids; ceramide; ceramide synthase; anticancer therapies
