Research use only. This article explains published laboratory and mouse research. It does not describe a treatment for people. JXL-069 is an experimental research compound that is not approved and has no human safety data.
The short version
In 2017, a UCLA team showed in mice that hair follicle stem cells depend on producing lactate to wake up and start a new hair cycle. Switching off the enzyme that makes lactate kept the stem cells asleep; pushing cells to make more lactate woke them sooner. This finding is the scientific basis for research on mitochondrial pyruvate carrier (MPC) inhibitors such as JXL-069 and PP405.
Where hair follicle stem cells live
Each hair follicle contains a reservoir of stem cells in a region called the bulge. In 1990, Cotsarelis, Sun and Lavker found slow-cycling, label-retaining cells in the bulge of mouse follicles and proposed that these are the follicle’s stem cells (Cotsarelis et al., 1990). These cells supply the new cells needed each time a follicle regrows its hair shaft.
The hair cycle in brief
Hair follicles cycle through three main phases: anagen (growth), catagen (regression) and telogen (rest). The stages are well defined in mice, where researchers use standard criteria to classify them (Müller-Röver et al., 2001). The key event for this topic is the switch from telogen to anagen, which requires the bulge stem cells to activate.
The 2017 lactate study
Flores and colleagues, working in the labs of Heather Christofk and William Lowry, asked what metabolic change accompanies stem cell activation. Their study in mice reported several connected findings (Flores et al., 2017):
- When the gene for lactate dehydrogenase A (Ldha) was deleted in hair follicle stem cells, the cells failed to activate and most follicles stayed in telogen.
- When the gene for the mitochondrial pyruvate carrier (Mpc1) was deleted in the same cells, lactate production went up and the switch from telogen to anagen came sooner.
- Applying UK5099, a chemical MPC inhibitor, to the skin also sped up the hair cycle in mice.
- A second compound, RCGD423, activated JAK-STAT3 signalling, raised Myc levels and Ldha expression, and also sped up the hair cycle when applied topically.
Why lactate matters
Cells turn glucose into pyruvate. Pyruvate can enter mitochondria through the MPC, or be converted into lactate by lactate dehydrogenase. The 2017 study suggests that in mouse hair follicle stem cells, the balance between these two routes acts as a switch: more lactate production is linked to activation. Blocking the MPC tips pyruvate towards lactate, which is why MPC inhibitors became a research focus.
From the lactate finding to JXL-069 and PP405
The same UCLA groups, with chemist Michael Jung, then made a series of new MPC inhibitors based on UK5099. JXL069 was one of the most potent in their cell assays (Liu et al., 2021). Pelage Pharmaceuticals, founded by these researchers, is testing a topical MPC inhibitor called PP405 in clinical trials. See What is JXL-069? and PP405 explained.
Limits of the evidence
- The stem cell and lactate findings come from mice. Mouse and human hair cycles differ in timing and regulation.
- Genetic deletion in mice is not the same as applying a compound.
- JXL-069 has no human data of any kind.
For in vitro and animal-model work on this pathway: JXL-069 raw powder and the JXL-069 (PP405) 0.05% w/v 30mL solution, for laboratory research only.
References
- Flores A, Schell J, Krall AS, et al. Lactate dehydrogenase activity drives hair follicle stem cell activation. Nat Cell Biol. 2017;19(9):1017-1026. doi:10.1038/ncb3575
- Cotsarelis G, Sun TT, Lavker RM. Label-retaining cells reside in the bulge area of pilosebaceous unit: implications for follicular stem cells, hair cycle, and skin carcinogenesis. Cell. 1990;61(7):1329-1337. doi:10.1016/0092-8674(90)90696-c
- Müller-Röver S, Handjiski B, van der Veen C, et al. A comprehensive guide for the accurate classification of murine hair follicles in distinct hair cycle stages. J Invest Dermatol. 2001;117(1):3-15. doi:10.1046/j.0022-202x.2001.01377.x
- Liu X, Flores AA, Situ L, et al. Development of Novel Mitochondrial Pyruvate Carrier Inhibitors to Treat Hair Loss. J Med Chem. 2021;64(4):2046-2063. doi:10.1021/acs.jmedchem.0c01570
