PP405 Possible Breakthrough Treatment for Hair Loss

[BadassBlues]

This looks promising!

UCLA Scientists Unveil PP405 Molecule, Promising Breakthrough in Hair Restoration Therapy | University Cube

UCLA scientists have unveiled PP405, a molecule that reactivates dormant hair follicle stem cells, offering a groundbreaking and potentially transformative solution for millions affected by pattern baldness globally.

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UCLA Scientists Unveil PP405 Molecule, Promising Breakthrough in Hair Restoration Therapy​

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Key Takeaways
3/26/2025
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Medicine
A groundbreaking discovery from UCLA scientists is poised to transform the landscape of hair restoration. Researchers have unveiled a molecule, PP405, which has shown remarkable potential in clinical trials to awaken dormant yet undamaged hair follicles, promising a new frontier in the treatment of pattern baldness. This revelation comes at a time when current FDA-approved treatments, such as minoxidil and finasteride, remain constrained by limited efficacy, benefiting only a fraction of patients. The introduction of PP405 offers hope for a more robust and inclusive approach to combating hair loss, a condition that affects millions globally and carries profound emotional and social ramifications.

Hair loss, particularly androgenetic alopecia or pattern baldness, has long been a vexing challenge for both patients and medical professionals. Despite advances in dermatology, existing treatments often fall short, leaving many to explore supplemental therapies such as red light therapy, platelet-rich plasma injections, or costly hair transplantation procedures. These options, while innovative, are neither curative nor universally accessible, often requiring significant time and financial investment. Against this backdrop, UCLA’s discovery of PP405 represents a potentially transformative leap forward.

The molecule’s mechanism is rooted in the unique metabolic activity of hair follicle stem cells, which play a critical role in hair growth cycles. Scientists have long understood that these stem cells can become dormant due to aging, hormonal changes, or other environmental factors, leading to thinning hair or complete baldness. PP405, however, appears capable of reactivating these inactive cells, effectively jumpstarting the process of hair regrowth. Early clinical trials have demonstrated promising results, with patients experiencing noticeable improvements in hair density and coverage.

What sets PP405 apart is its ability to complement existing therapies rather than replace them. For individuals already using minoxidil or finasteride, the molecule could amplify the efficacy of these treatments, offering a synergistic effect that enhances overall outcomes. This adaptability positions PP405 as a versatile tool in the expanding arsenal of hair restoration solutions, which increasingly emphasize personalized approaches tailored to individual needs.

The timing of this breakthrough is particularly noteworthy, as demand for hair restoration services continues to surge. Experts liken the growing accessibility of modern therapies to the rise of Botox in cosmetic medicine—once a niche procedure, now a mainstream preventive care option. This parallel underscores a cultural shift in attitudes toward aesthetic interventions, where proactive measures are increasingly embraced to preserve youthfulness and confidence.

However, the promise of PP405 also highlights the importance of early intervention and evidence-based treatment strategies. Dermatologists and researchers alike stress the need for patients to seek professional consultation at the first signs of hair thinning, rather than relying on over-the-counter solutions or unproven remedies. Timely diagnosis and treatment not only improve outcomes but also mitigate the psychological impact of hair loss, which can erode self-esteem and social comfort.

Beyond its immediate clinical implications, the development of PP405 signals a broader evolution in the science of regenerative medicine. Hair restoration, once dismissed as a superficial concern, is now recognized as a legitimate field of medical inquiry, intersecting with stem cell research, metabolic studies, and pharmaceutical innovation. The molecule’s success could pave the way for similar advancements in other areas of regenerative therapy, from skin rejuvenation to organ repair.

Moreover, the societal implications of accessible hair restoration therapies warrant consideration. As treatments like PP405 become more widely available, they could democratize the pursuit of aesthetic enhancements, leveling the playing field for individuals across socioeconomic boundaries. At the same time, the normalization of such interventions raises questions about beauty standards and the pressures to conform to ideals of youth and vitality.

In the end, UCLA’s discovery of PP405 is more than a scientific milestone—it is a testament to the power of curiosity and innovation to address deeply human concerns. While the molecule’s journey from laboratory to widespread application is still unfolding, its potential to reshape the narrative of hair loss is undeniable. For those who have long sought solutions to the challenges of pattern baldness, PP405 offers not just hope, but the possibility of reclaiming something profoundly personal—the confidence to feel comfortable in one’s own skin.

 

[Cataceous]

Still a ways off with the Phase 2A trial just getting started. If it continues to look good then it may show up on research chemical sites before FDA approval, depending on its legal status.

 

[Vince]

I'm sure the price will be crazy high like every new drug.

 

[BadassBlues]

The potential to add this to the already effective Minoxidil / Finasteride topical sounds like a possible winner. I use a blend of this with 15% Minoxidil and 1% Finasteride. I have had very good results.

 

[BadassBlues]

Pelage Presents Late-Breaking Data at AAD 2024 Meeting Demonstrating PP405 Activates Human Hair Follicle Stem Cells Ex Vivo and in Phase 1 Clinical Study

/PRNewswire/ -- Pelage Pharmaceuticals, a clinical-stage regenerative medicine company pioneering a new generation of treatments for hair loss, today presented...

www.prnewswire.com

PP405 is a potent topical mitochondrial pyruvate carrier (MPC) inhibitor that acts on the cellular metabolic pathway to upregulate lactate dehydrogenase (LDH), which stem cells are particularly sensitive to, resulting in their activation and hair growth.​

 

[BadassBlues]

Structures and mechanism of human mitochondrial pyruvate carrier​

• Jiaming Liang,
• Junhui Shi,
• Ailong Song,
• Meihua Lu,
• Kairan Zhang,
• Meng Xu,
• Gaoxingyu Huang,
• Peilong Lu,
• Xudong Wu &
• Dan Ma

Nature (2025)Cite this article

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We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Abstract​

Mitochondrial pyruvate carrier (MPC) is a mitochondrial inner membrane protein complex essential for uptake of pyruvate into matrix as the primary carbon source for tricarboxylic acid (TCA) cycle1,2. Here, we report six cryo-EM structures of human MPC in three different states: three structures obtained at different conditions in intermembrane space (IMS)-open state with highest resolution of 3.2 Å, a structure of pyruvate-treated MPC in occluded state at 3.7 Å, and two structures in matrix-facing state bound with the inhibitor UK5099 or an inhibitory nanobody on the matrix side at 3.2 Å and 3.0 Å, respectively. MPC is assigned into a heterodimer consisting of MPC1 and MPC2, with the transmembrane domain adopting pseudo-C2-symmetry. Approximate rigid body movements occur between the IMS-open state and the occluded state, while structural changes primarily on the matrix side facilitate the transition between the occluded state and the matrix-facing state, revealing the alternating access mechanism during pyruvate transport. In the UK5099-bound structure, the inhibitor fits well and interacts extensively with a pocket that opens to the matrix side. Our findings provide important insights into the mechanisms underlying MPC-mediated substrate transport, and the recognition and inhibition by UK5099, which will facilitate future drug development targeting MPC.

 

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Biochemistry, Lactate Dehydrogenase - StatPearls - NCBI Bookshelf

Biochemistry, Lactate Dehydrogenase​

Aisha Farhana; Sarah L. Lappin.

Author Information and Affiliations

Last Update: May 1, 2023.
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Introduction​

Lactate dehydrogenase (LDH) is an important enzyme of the anaerobic metabolic pathway. It belongs to the class of oxidoreductases, with an enzyme commission number EC 1.1.1.27. The function of the enzyme is to catalyze the reversible conversion of lactate to pyruvate with the reduction of NAD+ to NADH and vice versa.[1] The enzyme is present in a variety of organisms, that include plants and animals. It is ubiquitously present in all tissues and serves as an important checkpoint of gluconeogenesis and DNA metabolism. A species-wide analysis of LDH demonstrates its well-preserved structure with only a few changes in the amino acid sequence across species.[2] The structural similarity with slight amino acid changes provides a logical platform for designing functional molecules to modulate the catalytic potential and expression of the enzyme. This article will focus on the biochemical function, testing methods, and clinical relevance of the LDH enzyme.
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Issues of Concern​

Lactate dehydrogenase is an enzyme that is present in almost all body tissues. Conditions that can cause increased LDH in the blood may include liver disease, anemia, heart attack, bone fractures, muscle trauma, cancers, and infections such as encephalitis, meningitis, encephalitis, and HIV. LDH is also a non-specific marker of tissue turnover, which is a normal metabolic process. Many cancers cause a general increase in LDH levels or an increase in one of its isozymes. Thus it can be a non-specific tumor marker not useful in identifying the type of cancer. Because LDH is non-specific and routine isozyme measurement is usually unavailable in clinical laboratories, LDH measurements provide incomplete information, and alternate assays such as CK for muscle, ALT for liver, troponin for heart diseases, etc. are needed.

Additionally, LDH activity is affected by hemolysis of the blood sample. Since red blood cells (RBCs) contain their own LDH protein, hemolysis causes an artifactual increase leading to false-positive high results. Besides, any cellular necrosis can result in increased serum concentration, and its ubiquitous distribution throughout tissues confers a severe handicap to its wider clinical utility as a biomarker.
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Cellular Level​

LDH is a cytoplasmic enzyme that is present in almost all tissues but at high concentrations in muscle, liver, and kidney. Red blood cells also contain moderate concentrations of this enzyme. LDH exhibits five isomeric forms assembled in tetramers of either of the two types of subunits, namely muscle (M) and heart (H). The isoforms called isozymes are named LDH-1 through LDH-5, each having differential expression in different tissues.[3] This differential expression of LDH is the basis of its importance as a clinical diagnostic marker. Isozyme LDH-1 has four heart subunits (4H) and is the major isozyme present in the heart tissue. Isozyme LDH-2 has three heart and one muscle subunit (3H1M) and is the major isozyme of the reticuloendothelial system and RBCs. The LDH-3 isozyme consists of two heart and two muscle subunits (2H2M) and is the major isozyme of the lungs. Isozyme LDH-4 has one heart and three muscle subunits (1H3M) and is the primary isozyme present in the kidneys. The LDH-5 isozyme has four muscle subunits (4M) and has significant expression in liver and skeletal muscle.[4][5] These five isoforms, although catalyzing the same overall reaction, differ in their affinity to the substrate, inhibition concentration, isoelectric point, and electrophoretic mobility. These five isoforms can be visualized in the active state using LDH zymography.

Though LDH is predominantly a cytoplasmic enzyme, its mitochondrial presence is also demonstrated by various studies. The presence of a mitochondrial L-lactate dehydrogenase (mL-LDH) was confirmed in yeast, plant, and animals.[6] L-lactate, which is the substrate for mL-LDH, is transported to the mitochondria through L-lactate/H symporter and the L-lactate/pyruvate and L-lactate/oxaloacetate antiporters. Subsequently, mL-LDH facilitates the oxidation of L-lactate to pyruvate in the mitochondrial matrix.[7] Many cancer cells reprogram the mitochondrial processes to fulfill their higher demands for energy. Glycolysis becomes elevated in cancer cells, and hence, mL-LDH may be a player in accelerating oxidative phosphorylation.[8]
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Molecular Level​

The genes that encode LDH are LDHA, LDHB, LDHC, and LDHD. LDHA, LDHB, and LDHC encode for L-isomers of the enzyme, whereas LDHD encodes the D-isomer. The L-isomers use and produce L-lactate, which is the major enantiomeric form of lactate present in the vertebrates. The gene that encodes the LDHA form of the enzyme is located on chromosome 11p15.4 and is transcribed into a 332 amino acid protein. The LDHB gene is located on chromosome 12p12.1 and encodes a protein of 334 amino acids. The isozyme forms of Lactate dehydrogenase enzymes, LDH-1 through LDH-5 are translational products of two genes LDHA and LDHB gene [9]. The two genes provide instructions for making the lactate dehydrogenase-A and lactate dehydrogenase-B subunits of the lactate dehydrogenase enzyme. There are five different forms of LDH, each made up of four subunits. Various combinations of the protein products of lactate dehydrogenase-A subunits and lactate dehydrogenase-B subunits produced from a different gene) make up the different forms of the enzyme.[4]

In the mammalian system, two more subunits, LDHC and LDHBx, are also included to form LDH tetramer. The LDHC gene encodes the LDHC protein that is specific to the testes, while the LDHBx gene encodes the LDHBx protein specific to the peroxisome.[10] LDHBx is the readthrough form of the LDHB gene. LDHBx is generated by translation of the LDHB mRNA, where the stop codon is read as encoding an amino acid. Consequently, translation proceeds to the next stop codon, which adds seven amino acid residues encoding the peroxisomal targeting signal to the normal LDH-H protein so that LDHBx is imported into the peroxisome.[11] The secondary structure of LDH comprises 40% alpha helices and 23% beta-sheets; this makes LDH as mixed beta-alpha-beta, with parallel beta sheets as the main component of the protein structure.[12]

The active site of the enzyme is located in its substrate-binding pocket and contains catalytically important His-193 as well as Asp-168, Arg-171, Thr-246, and Arg-106. His-193 is the active amino acid present in the active site of humans as well as other species of the animal kingdom. All the LDH isozymes are structurally very similar; however, each one has distinct kinetic properties resulting from the differences in the charged amino acids flanking the active site [2][13].

The two different subunits of LDH (the M subunit and H subunit of LDH) both maintain the same active site structure and amino acids that participate in the reaction. In the tertiary structure, the alanine of the M-chain is replaced with glutamine in the H-chain. Alanine is a nonpolar and small molecular weight amino acid, while glutamine is a positively charged amino acid. This chemistry provides different biochemical properties to the two subunits. Hence, the H subunit can bind faster but has fivefold reduced catalytic activity as compared to the M-subunit. LDHA subunit carries a net charge of -6 and exhibits a higher affinity towards pyruvate, thus converting pyruvate to lactate and NADH to NAD+. On the other hand, LDHB has a net charge of +1 and demonstrates a higher affinity towards lactate, resulting in a preferential conversion of lactate to pyruvate and NAD+ to NADH.[4]

LDH is inherent in maintaining homeostasis when there is a lack of oxygen. Oxygen levels in the muscle tissues drop quickly upon heavy exercise. Since oxygen is typically the final electron acceptor of the electron transport chain (ETC), the chain halts along with ATP synthase. Nonetheless, muscle cells continue to function by creating ATP through NAD+. LDH produces lactic acid as an end product through a fermentation reaction. In the process, LDH removes electrons from NADH and makes NAD+, which is channelized in the glycolysis pathway to create ATP.[1] Though this process creates less ATP as compared to the ETC, it allows the cell to carry out its physiological and biochemical functions in the absence of oxygen.
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Function​

Lactate Dehydrogenase is one of the H transfer (oxidoreductase) enzymes, which catalyzes the reversible conversion of pyruvate to lactate using NADH. Basically, the enzyme is involved in the anaerobic metabolism of glucose when oxygen is absent or in limited supply.[14]

• Pyruvate + NADH + H+ --> Lactate + NAD+

When cells become exposed to anaerobic or hypoxic conditions, the production of ATP by oxidative phosphorylation becomes disrupted. This process demands cells to produce energy by alternate metabolism. Consequently, LDH is upregulated in such conditions to cater to the need for energy production. However, lactate produced during the anaerobic conversion of glucose meets a dead end in metabolism. It cannot undergo further metabolism in any tissue except the liver. Hence, lactate is released in the blood and transported to the liver, where LDH performs the reverse reaction of converting lactate to pyruvate through the Cori cycle.[6]

During exercise, when muscles exhaust the oxygen, pyruvate gets catalyzed into lactic acid by the lactate dehydrogenase enzyme. In erythrocytes, pyruvate is not further metabolized due to the absence of mitochondria but remains within the cytoplasm, finally converting to lactate. In this reaction, NADH oxidizes to NAD+. The availability of high intracellular concentrations of NAD is necessary to carry out the preparatory phase of glycolysis. The net ATP production of anaerobic glycolysis is only 2 ATP per glucose molecule as compared to oxidative phosphorylation, which produces 36 ATP per glucose molecule. LDH can also catalyze the dehydrogenation of 2-hydroxybutyrate, but it is the less preferred substrate for LDH than lactate.[14]

The subunit composition of the LDH enzyme (H and M subunits) varies among tissues (mentioned previously in the 'cellular' section). This variation is due to the difference in the metabolic rates, energy needs, and function of the tissues, which reflects in their LDHA: LDHB ratio. Almost 40% of lactate in the circulation is released from the skeletal muscle. This lactate is further absorbed mostly by the liver and kidney, where it undergoes oxidation for the synthesis of glucose. In the brain, about 10% of the lactate oxidizes to fuel 8% of cerebral energy needs during resting conditions, and the remaining lactate is released in circulation.[14][15] However, hyperlactatemia and physical exertion can lead to the uptake of lactate, which supports 60% of brain metabolism, with the contribution of cerebral lactate oxidation only up to 33%.

In cancer cells, the function of LDH, specifically LDHA, is modified as compared to the normal cells. Cancer cells employ LDH to increase their aerobic metabolism (glycolysis and ATP production, and lactate production) even in the presence of oxygen. This process is known as the Warburg effect. The abnormal cancer cells benefit from switching to anaerobic metabolic phenotype by avoiding the generation of oxidative stress by the ETC. Additionally, the cancer cells also gain access to the metabolic intermediates of the tricarboxylic acid cycle, generated through glucose and pyruvate, to synthesize lipids and nucleic acid for rapid cell proliferation.[16][17]
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Mechanism​

LDH catalyzes the synchronized inter-conversion of pyruvate to lactate and NADH to NAD+ and increases the speed of reaction by 14 times. The chemical reaction proceeds by transferring a hydride ion from NADH to pyruvate at its C2 carbon. The molecular mechanism involves the binding of NADH to the enzymes as a first step. Many residues at the active site are involved in this binding. Once NADH is bound, it facilitates the binding of lactate, through an interaction between the NADH ring and the LDH residues. Transfer of a hydride quickly occurs in both directions forming two tertiary complexes, namely, LDH-NAD+-lactate and LDH-NADH-pyruvate.[18] Subsequently, pyruvate Is dissociated from the enzyme first, and then NAD+ is released. The rate of dissociation of NADH and NAD+ proves to be the rate-limiting step in this reaction, and the final conversion of pyruvate to lactate leading to the regeneration of NAD+ is thermodynamically favored in the reaction.[19]

Enzyme regulation: LDH activity is dependant on the metabolic switch to anaerobic respiration. LDH is modulated by three types of regulations, namely, allosteric modulation, substrate-level regulation, and transcriptional regulation. The relative availability and concentration of substrates regulate the activity of LDH. The enzyme becomes more active during extreme muscular activity when there is an increase in substrates. The demand for ATP compared to aerobic ATP supply causes the accumulation of ADP, AMP, and Pi. Glycolytic flux leads to the production of pyruvate that exceeds the metabolic capacity of pyruvate dehydrogenase and other shuttle enzymes that metabolize pyruvate. This process channelizes the flux of pyruvate and NAD+ through LDH, subsequently generating lactate and NADH.[20]

In conditions of increased NADH/NAD+ ratio, as usually happens in individuals who drink alcoholic beverages, high concentrations of ethanol lead to the production of high concentrations of lactate and NADH, and thus the depletion of NAD+. This reaction subsequently leads to pyruvate conversion to lactate linked to the regeneration of NAD+. Thus, the high NADH/NAD+ ratio shifts the LDH equilibrium towards lactate.[20]