453: Efavirenz slows sCJD progression by reshaping brain cholesterol

Ali T et al., JCI Insight - Repurposed low-dose efavirenz slowed disease progression and extended survival in tg650 mice inoculated with MM1 sCJD prions by activating CYP46A1, raising 24S‑hydroxycholesterol and reducing PrPSc, brain cholesterol and lipid droplets at the early clinical stage. Key terms: efavirenz, CYP46A1, Creutzfeldt-Jakob disease, cholesterol metabolism, prion disease.

⚠️ Important: nothing in this episode is a reason to take efavirenz.
Efavirenz is a prescription antiretroviral with real side effects, including sleep disturbance, vivid dreams, dizziness and psychiatric effects. The dose used in this study — about 0.09 mg/kg per day — is roughly 300 to 400 times lower than the dose prescribed for HIV, and is not something anyone can approximate on their own. No human being has yet been shown to benefit from efavirenz for prion disease. A Phase 3 trial is registered as NCT07482085 on ClinicalTrials.gov and has not reported results. If prion disease affects you or your family, talk to a neurologist and ask about registered trials — not about a pharmacy.
This episode is the fourth in our series on Creutzfeldt-Jakob disease, which began as a dedication to Lito Sousa. Every trial named in the series is registered publicly on ClinicalTrials.gov.

Study Highlights:
Oral low-dose efavirenz given to human-PrP–overexpressing tg650 mice starting at 30 or 130 days postinoculation significantly slowed clinical progression and extended survival by 17 and 23 days, respectively. At the early clinical stage EFV-treated mice showed reduced PK-resistant PrPSc, decreased brain cholesterol and lipid droplets, and increased CYP46A1 expression with higher 24S‑hydroxycholesterol in brain and serum. Overexpression of CYP46A1 in prion-infected neuronal cells likewise reduced PrPSc, supporting a causal link between CYP46A1 activation and antiprion effects.

Conclusion:
Low-dose oral efavirenz activates CYP46A1, restores cholesterol turnover, reduces early PrPSc accumulation and lipid pathology, and extends survival in a humanized sCJD mouse model, supporting EFV as a candidate for further evaluation in human prion disease.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
Treatment with efavirenz extends survival in a Creutzfeldt-Jakob disease model by regulating brain cholesterol metabolism

First author:
Ali T

Journal:
JCI Insight

DOI:
10.1172/jci.insight.190296

Reference:
Ali T, Cashion J, Hannaoui S, Ahmed-Hassan H, Schatzl H, Gilch S. Treatment with efavirenz extends survival in a Creutzfeldt-Jakob disease model by regulating brain cholesterol metabolism. JCI Insight. 2025;10(14):e190296. https://doi.org/10.1172/jci.insight.190296.

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

Support:
Base by Base is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming:
❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01
☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00
More at basebybase.com

On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/efavirenz-prion-cjd-cholesterol

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-08-31.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript's core biomedical claims about EFV's e...