**11. Conclusions**

Fingolimod and Miglustat are FDA-approved medications related to the biochemistry of endogenous SLs. Targeting enzymes involved in SL biosynthesis, metabolism, and catabolism show promising hits for drug discovery efforts based on sphingolipidomics. Currently, there are several molecules in clinical studies that push our understanding of the SL biology in several disease states, mainly cancer. As discussed, a functional lipid raft is made of SLs. Small molecules and biologics targeting the signaling proteins embedded in these lipid rafts and the relevance of these proteins in terms of sphingolipid flux is fertile for future investigations. So far, the strategies aimed at increasing cellular Cer have opened up an avenue for perturbing cellular ceramide biosynthesis and metabolism. Of the several hallmarks of cancer that promote chemoresistance, targeting Cer-metabolizing enzymes appears to be a promising drug target. The molecular objective is to increase cellular Cer, and this has opened a new avenue of targeting resistant cancers based on membrane trafficking. Using a combination approach along with FDA-approved regimens has promising applications.

**Author Contributions:** Conceptualization, F.A., S.M. and S.P.; resources, S.P., J.C.K.L. and J.J.B.; writing—original draft preparation, F.A., S.M., J.O., J.C.K.L., J.J.B. and S.P.; writing—review and editing, F.A., S.M., J.O., J.C.K.L., J.J.B. and S.P.; visualization, F.A., S.M., J.O., J.C.K.L., J.J.B. and S.P.; supervision, S.P.; funding acquisition, S.P. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was supported, in part, by funds from Biomedical and Pharmaceutical Sciences, College of Pharmacy, Idaho State University; the National Science Foundation (NSF) MRI grant CHE-2019074; the American Association of Colleges of Pharmacy NIA award—2023; the Office of Research—ISU (LIGS33); the Pardee Foundation Grant; and the Institute for Modeling Collaboration and Innovation, University of Idaho, COBRE: P20GM104420 for chemdraw software, INBRE Program NIH grant number P20GM103408 (National Institute of General Medical Sciences).

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Acknowledgments:** We wish to thank Apurbha Dutta, School of Pharmacy, The University of Kansas, and Webster L. Santos, Chemistry Department, Virginia Tech, for their continued intellectual support in sphingolipid biochemistry; collaborator Ali Aghazadeh Habashi; and Amy E. Bryant, Marvin K. Schulte, and Kavita Sharma, Biomedical and Pharmaceutical Sciences, Idaho State University, Pocatello, ID, for their interest and support. The authors apologize to those investigators whose publications were not mentioned in this review due to space limitations.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **Abbreviations**

