Halofuginone - ITP 9% Increase in Mouse Lifespan (Males)

DeStrider · September 4, 2025, 12:36am

Halofuginone is a synthetic, anti-parasitic drug, a derivative of the plant-derived alkaloid febrifugine, used in veterinary medicine to treat coccidiosis and cryptosporidiosis. It works by inhibiting prolyl-tRNA synthetase (ProRS), a crucial enzyme in protein synthesis. Beyond its antiparasitic use, halofuginone has demonstrated potential as a treatment for fibrosis, cancer, and autoimmune disorders by inhibiting collagen synthesis and angiogenesis, as well as by modulating the TGF-β signaling pathway.

Uses

Veterinary Medicine:

Halofuginone is used as a coccidiostat and in the treatment of parasitic infections in animals, such as cryptosporidiosis in calves.

Human Medicine (Investigational):

It is being investigated for its potential to treat various human diseases, including:

Cancer: By inhibiting tumor progression and metastasis.
Fibrosis: By suppressing collagen synthesis and fibroblast activation.
Autoimmune Disorders: By modulating immune cell differentiation.
Obesity: By influencing metabolic pathways and hormone levels.

Mechanism of Action

Halofuginone has a multifaceted mechanism of action:

Inhibition of Prolyl-tRNA Synthetase (ProRS):

Halofuginone inhibits ProRS, a key enzyme in protein synthesis, which is vital for combating parasitic infections like malaria and cryptosporidiosis.

Inhibition of Fibrosis and Angiogenesis:

It inhibits the expression of collagen type I and Matrix Metalloproteinase 2 (MMP-2), and suppresses the TGF-β/Smad3 signaling pathway, which is involved in fibrosis and tumor metastasis.

Immune Modulation:

It can inhibit the differentiation of pro-inflammatory Th17 cells and modulate amino acid starvation responses, suggesting potential benefits for autoimmune disorders.

Origin

Natural Source:

Halofuginone is a synthetic derivative of febrifugine, a quinazolinone alkaloid found in the Chinese herb Dichroa febrifuga, which has been used in traditional Chinese medicine for centuries.

Synthesis:

Halofuginone was synthesized to reduce the toxicity associated with the natural febrifugine, making it suitable for therapeutic use in animals and human clinical trials.

DeStrider · September 4, 2025, 12:42am

The primary side effects of halofuginone in humans are nausea, vomiting, fatigue, and in some cases, bleeding complications. Other reported adverse events include diarrhea, constipation, anorexia, and liver toxicity. Due to these side effects, particularly the potential for liver toxicity, halofuginone has not translated into a widely used clinical medicine.

Common Side Effects

Gastrointestinal issues: Nausea and vomiting are frequently reported.
General fatigue: Patients may experience a general feeling of tiredness.
Bleeding complications: Some patients have experienced bleeding problems.
Digestive issues: Diarrhea and constipation have also been observed.

Other Reported Effects

Anorexia: A loss of appetite has been noted.
Liver toxicity: Halofuginone can cause damage to the liver.
Dehydration and prostration: These effects have been linked to higher doses of the drug.

Why Halofuginone is not widely used

Promising activity but significant side effects:

While halofuginone has shown promising biological activity, its side effect profile has limited its clinical application.

Limited therapeutic use:

Despite being studied, it has not been developed into a commonly used therapeutic drug for humans.

In summary: While halofuginone shows potential in certain research areas, its side effects, especially nausea, vomiting, fatigue, and potential liver toxicity, have restricted its use as a human medicine.

DeStrider · September 4, 2025, 12:43am

Based on the potential side effects and a quick dive into this drug, I think I’ll skip this one. Unless there is something I’m missing.

RapAdmin · September 4, 2025, 3:40am

Interesting! Halofuginone inhibits protein synthesis, a little bit like rapamycin perhaps.

It is not available for purchase in India, from what I can see.

Is halofuginone FDA approved?

Halofuginone, a synthetic derivative of a plant-alkaloid febrifugine, has shown anti-fibrotic and type I collagen synthesis inhibitory activities (McGaha et al., 2002). It has been granted approval by FDA for the treatment of scleroderma.

What is the mechanism of action of halofuginone?

AI Overview

Halofuginone works by inhibiting prolyl-tRNA synthetase (ProRS). This enzyme is crucial for protein synthesis, as it “charges” prolyl-tRNA with proline, making it ready for protein production. By inhibiting this process, halofuginone causes an accumulation of uncharged tRNAs, mimicking an amino acid starvation response. This response leads to various effects, including the suppression of pro-inflammatory T helper 17 (Th17) cells, a reduction in collagen production and fibrosis, and inhibition of tumor growth.

More info:

Detailed Mechanism of Action

1. Enzyme inhibition:

Halofuginone binds to the active site of prolyl-tRNA synthetase (ProRS), a component of the glutamyl-prolyl-tRNA synthetase (EPRS) complex.

1. ATP-dependent binding:

This binding is ATP-dependent, with halofuginone occupying the positions of both the bound proline and the 3’ end of the tRNA.

1. Prolyl-tRNA charging blockage:

By blocking ProRS, halofuginone prevents the charging of tRNA with proline, a process essential for the incorporation of proline into proteins.

1. Amino acid starvation response (AAR):

The accumulation of uncharged tRNAs triggers the cell’s amino acid starvation response (AAR).

1. Therapeutic effects:

The AAR pathway activation has several downstream consequences, including:

Immunomodulation: Selectively inhibits the differentiation of pro-inflammatory Th17 cells, which are involved in autoimmune diseases.
Anti-fibrotic effects: Reduces the synthesis of collagen and extracellular matrix proteins, inhibiting fibrosis.
Anti-tumor effects: Suppresses collagen type I expression and other factors that support tumor growth and invasiveness.

RapAdmin · September 21, 2025, 6:35pm

What is Halofuginone / How it Works

Halofuginone is a synthetic quinazolinone derivative originally isolated as a derivative of febrifugine. (PubMed)
One of its key mechanisms: inhibition of prolyl-tRNA synthetase, which leads to an “amino acid starvation response” when proline-charging of tRNAs is reduced. This in turn has downstream effects including reduced collagen production, reduced certain immune responses, etc. (PubMed)
It also down-regulates expression of collagen type I (alpha1(I)), matrix metalloproteinase-2 (MMP-2), and tends to reduce fibrosis, tissue remodeling, and possibly tumor stroma and metastasis. (DrugBank)

Potential Benefits / Therapeutic Effects

These are the main areas (animal, preclinical, veterinary, and some human) in which halofuginone has shown promise:

Indication / Area	What Studies Show / Effects
Antiprotozoal / antiparasitic	Effective in animals (especially in veterinary settings) against Cryptosporidium parvum (e.g. in newborn calves) to reduce diarrhea, oocyst shedding, mortality, and improve weight gain. (PubMed) Also studied in malaria, leishmaniasis, toxoplasmosis. (PubMed)
Fibrosis / anti-fibrotic	Inhibition of collagen I expression and extracellular matrix deposition suggests it could be useful in fibrotic diseases. Some preclinical work confirms this. (DrugBank)
Cancer / Tumor suppression	Some animal models show suppression of tumor progression, metastasis, possibly via reducing stromal support, invasiveness, angiogenesis. (DrugBank)
Autoimmune / Immune modulation	Halofuginone appears to reduce differentiation of Th17 cells (a T helper subtype implicated in some autoimmune diseases), without broadly suppressing other immune cell types. (Wikipedia)
Obesity / Metabolic effects	In recent mice studies (diet-induced obesity), it suppressed food intake, increased energy expenditure, and caused weight loss; also improved measures of insulin and metabolic health. (Science)
Potential antiviral / COVID-19	Has shown in vitro activity against SARS-CoV-2 (virus adhesion/blocking) and is being tested in human trials. In a Phase II trial in mild/moderate COVID-19 (non-hospitalized), different doses (0.5 mg, 1 mg) were compared with placebo. While viral load decay did not differ significantly, there was evidence of more respiratory symptom-free days (especially cough) in the halofuginone groups. (PLOS)

Known Side Effects / Risks / Limitations

These are what have been observed, or what are concerns. Some are from human trials; others from animal or veterinary use.

Gastrointestinal symptoms: Nausea, vomiting are among the most commonly reported side effects in human studies. (PLOS)
Liver toxicity: In some preclinical/human data, elevated risk of toxicity to the liver has been seen. (ScienceDirect)
Bleeding risk: There is some suggestion (in earlier trials) of possible increased bleeding or altered coagulation, though more recent trials (e.g. the COVID-19 trial) did not find a significant increase in bleeding. (PLOS)
Toxicity in veterinary use: In calves, if given to weak animals or those with prolonged diarrhea (>24 hours), risk/side effects are higher. Also concerns with handling (skin/eye irritation or allergy) for those administering; residue and withdrawal periods are relevant for meat safety. (European Medicines Agency (EMA))
Limitations of human data: Many of the promising effects are in animals or in vitro. Human trials are limited, small in size; certain endpoints (e.g. viral load decay for COVID-19) have not been met. (PLOS)
Dose-related toxicity: As with many drugs, higher doses appear to increase side-effects, especially GI issues. There may also be issues with long-term administration, though that is less well characterized. (PLOS)

Unknowns / Challenges

The full safety profile in humans (especially long-term) remains incompletely defined.
Exact mechanisms in some therapeutic settings are still being elucidated (e.g. how the immune modulation and fibrosis inhibition interplay in human disease).
Optimal dosing, route of administration, enantiomer effects (there is some data that one enantiomer may be more biologically active) need clarification. (PLOS)
Potential for off-target effects, especially given that inhibition of tRNA charging is somewhat of a broad cellular stress signal.

If you like, I can send you a table comparing all of the human trial data side by side: dosages, adverse events, effect sizes. Do you want that?

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Here’s a concise catalog of the human clinical studies that have tested halofuginone (or its oral DR formulation “HT-100”) to date, grouped by indication and listed with design, dose, size, outcomes, and safety. I’m including both completed, published trials and registered/announced human studies with available details.

COVID-19 (completed, peer-reviewed)

Study	Design & N	Dose/Route	Primary outcomes	Main findings	Safety
HALOS Trial (2024)	Phase 2, multicenter, randomized, double-blind, placebo-controlled; N=148 outpatients with mild–moderate COVID-19	0.5 mg or 1 mg oral, once daily × 10 days	Viral-load decay; safety/tolerability	No significant difference in viral-load decay vs placebo. Exploratory: more cough-free days in HF groups; overall symptom trajectories similar.	Generally well tolerated; mostly GI events (nausea, vomiting). No excess serious AEs vs placebo. (PMC)

Fibrosis / Scleroderma / cGVHD (early human exposure, pilot data)

Study	Design & N	Formulation	Outcomes	Findings	Notes
Topical safety in healthy volunteers	Phase I, N=14 healthy adults	0.1% topical halofuginone	Local & systemic safety	Tolerated in a small Phase I exposure study.	Cited within a clinical review summarizing early human experience. (PubMed)
SSc pilot	Pilot, number not specified in abstract	Topical	Skin scores	“Reduction in skin scores” observed in SSc pilot.	Uncontrolled pilot referenced in review; details limited in public abstract. (PubMed)
cGVHD case & oral exposure study	Case report (dermal application) and oral administration study	Topical; oral	Collagen content; exposure	Dermal application reduced collagen at treated site in cGVHD patient; separate oral study reported tolerability and plasma levels above predicted therapeutic exposure.	Proof-of-mechanism/PK; not efficacy-powered. (PubMed)

Note: These fibrosis/cGVHD/SSc entries are the published human exposures cited in a peer-reviewed clinical review (not full RCTs). They establish early human tolerability, dermal pharmacology, and plausibility for anti-fibrotic use, but not definitive efficacy. (PubMed)

Duchenne Muscular Dystrophy (DMD) – HT-100 (delayed-release halofuginone)

Study	Design & N	Dose/Route	Status & topline	Notes
NCT01847573	Phase 1b/2a, dose-escalation in boys with DMD	Oral DR HT-100	Conducted 2013–2015; sponsors reported interim signals of biological activity and tolerability; program later paused and subsequently cleared to restart	Details mainly from sponsor/press and registry; peer-reviewed results not found. (ClinicalTrials)
NCT02525302	Open-label long-term extension for participants completing NCT01847573	Oral DR HT-100	Intended to collect longer-term safety/PK to inform dose	Registry record; no peer-reviewed outcomes located. (ClinicalTrials)

Oncology (Kaposi’s Sarcoma)

Study	Design & N	Dose/Route	Status	Notes
NCT00064142 (HIV-related Kaposi’s sarcoma)	Phase II	Halofuginone hydrobromide	Registered	Results not posted on the registry page; no peer-reviewed publication located from the record. (ClinicalTrials)

What this means (at a glance)

The only modern, fully powered, peer-reviewed randomized human trial is the 2024 HALOS outpatient COVID-19 study. It showed acceptable tolerability and no virologic efficacy on the primary endpoint, with a hint of symptom benefit (more cough-free days) that would require confirmation. (PMC)
Earlier human exposures (SSc/cGVHD/healthy-volunteer topical; small oral exposure work) support mechanism and tolerability but do not establish clinical efficacy for fibrosis in humans. (PubMed)
DMD (HT-100) reached Phase 1b/2a and an open-label extension; available information is from registries and sponsor communications, not peer-reviewed outcomes. (ClinicalTrials)
Kaposi’s sarcoma Phase II was registered; I couldn’t find posted results on the registry page or a linked publication. (ClinicalTrials)

If you’d like, I can turn this into a downloadable comparison table (dose, schedule, endpoints, effect sizes, AE rates) and keep it updated as new results appear.

A_User · September 21, 2025, 6:39pm

How actionable is this anyway? Are you going to combine all of the proven ITP study drugs although the combination hasn’t been studied in that model? On the other hand if there’s RCT’s in humans that could be informative in one way.

LukeMV · September 21, 2025, 10:10pm

I love how this is the first thing I looked for when I saw this ITP result as well

LukeMV · September 21, 2025, 10:11pm

I agree and I view Meclizine the same way as far as positive ITP results go. It just clues us in to potential mechanisms, if nothing else. Interesting results either way.