Pharmacology and Toxicology

In search of nonlipogenic ABCA1 inducers (NLAI): precision coregulator TR-FRET identifies diverse signatures for LXR ligands

1. Megan S Laham
2. Martha Ackerman-Berrier
3. Fahmida Alam
4. Sarah Turner
5. Ganga Reddy Velma
6. Christopher Penton
7. Soumya Reddy Musku
8. Manan Rana
9. Senthilkumar Thulasingam
10. Anandhan Annadurai
11. Maha Ibrahim Sulaiman
12. Nina Ma
13. Gregory RJ Thatcher

• Curated by eLife

  eLife Assessment

  The study curated a set of Liver X receptor ligands that may guide the design of future drugs that activate the Liver X receptor as potential therapeutics for cardiovascular disease, Alzheimer's and type 2 diabetes, without inducing mechanisms that promote fat/lipid production. The authors also present improved multiplexed precision CRT (coregulator TR-FRET) and cellular assays which allows measurement of ligand potencies to displace corepressors in the presence of coactivators, which cannot be achieved in a regular CRT assay. This makes the evidence presented compelling as it stretches beyond the current state-of-the-art, and these important findings are expected to have practical implications in many sub-fields and remain of interest to scientists working in cell and molecular biology, drug discovery, medicinal chemistry and pharmacology.

Reviewed by eLife

Large-scale synthetic data enable digital twins of human excitable cells

1. Pei-Chi Yang
2. Mao-Tsuen Jeng
3. Deborah K Lieu
4. Regan L Smithers
5. Gonzalo Hernandez-Hernandez
6. L Fernando Santana
7. Colleen E Clancy

• Curated by eLife

  eLife assessment:

  This important study presents a novel and technically robust framework that combines deep learning and optimized patch‑clamp protocols to infer biophysical parameters and generate electrophysiology‑based digital twins, with the inclusion of convincing experimental data being a clear strength; there is methodological innovation and potential impact for understanding cellular heterogeneity, drug response, and arrhythmia risk prediction. Concerns remain about clarity and validation, particularly regarding the biological meaning of the modeled heterogeneity, the selection and sufficiency of large synthetic training populations, and the robustness and uniqueness of inferred parameter sets. Most notably, key translational claims (e.g., replacing large‑scale wet experiments and predicting rare arrhythmic events) lack direct experimental validation and head‑to‑head comparisons with conventional protocols. Overall, while the approach is promising and timely, stronger biological grounding, clearer framing, and additional experimental validation are needed to support the manuscript's broad claims.

Reviewed by eLife

Identification of 14 Known Drugs as Inhibitors of the Main Protease of SARS-CoV-2

1. Mohammad M. Ghahremanpour
2. Julian Tirado-Rives
3. Maya Deshmukh
4. Joseph A. Ippolito
5. Chun-Hui Zhang
6. Israel Cabeza de Vaca
7. Maria-Elena Liosi
8. Karen S. Anderson
9. William L. Jorgensen

Reviewed by Rapid Reviews Infectious Diseases, ScreenIT

4-Aminoquinolines block heme iron reactivity and interfere with artemisinin action

1. Melissa Rosenthal
2. Daniel E Goldberg

• Curated by eLife

  eLife Assessment

  This is an important study with direct implications for the rational selection of antimalarial drug combinations. The authors present data demonstrating antagonism between 4-aminoquinoline antimalarials and peroxide drugs under physiologically relevant conditions, including robust effects at the trophozoite stage and for chloroquine at the ring stage. While the conclusions are based on in vitro assays and further work will be needed to fully resolve the underlying mechanism, the findings are convincing and provide a strong rationale for evaluating drug combinations in relevant preclinical models prior to clinical testing.

Reviewed by eLife

Magnesium isoglycyrrhizinate alleviates alcohol-associated liver disease through targeting HSD11B1

1. Lu Xiao
2. Lu Li
3. Shasha Wu
4. Zhaoyi Che
5. Yuyang Du
6. Jingyi Zheng
7. Jingsong Yan
8. Hao Wang
9. Hong Zhang
10. Yan Li
11. Jia Xiao

• Curated by eLife

  eLife Assessment

  This important study reports characterisation of hepatocyte molecular pathways affected by a glycyrrhizin derivative in both in vivo and in vitro mouse models of alcohol-associated liver disease. The authors show convincing evidence indicating that IPP delta isomerase 1 (Idi1) is an intermediate in these pharmacological effects, via the binding of the glycyrrhizin derivative to an upstream regulator of Idi1, HSD11B1, although some more quantitative analyses and better organisation of data would strengthen the study. The findings would be of interest to immunologists and pharmacologists interested in liver inflammation and its amelioration.

Reviewed by eLife

Snake venom metalloproteinases are predominantly responsible for the cytotoxic effects of certain African viper venoms

1. Keirah E. Bartlett
2. Adam Westhorpe
3. Mark C. Wilkinson
4. Nicholas R. Casewell

Reviewed by preLights

Single-cell transcriptomics identifies altered neutrophil dynamics and accentuated T-cell cytotoxicity in tobacco-flavored e-cigarette-exposed mouse lungs

1. Gagandeep Kaur
2. Thomas Lamb
3. Ariel Tjitropranoto
4. Irfan Rahman

• Curated by eLife

  eLife Assessment

  This manuscript by Kaur et al. identifies differential gene expression in distinct cell populations, specifically myeloid and lymphoid cells, following short-term exposure to e-cigarette aerosols with various flavors. Their findings are useful because they provide a single-cell sequencing data resource for assessing which genes and cellular pathways could be affected by e-cig aerosols and their components. However, the evidence is incomplete due to limited number of biological replicates per condition, as well as due to the lack of in vivo validation.

Reviewed by eLife

In vitro pharmacokinetics and pharmacodynamics of the diarylquinoline TBAJ-587 and its metabolites against Mycobacterium tuberculosis

1. Diana Angelica Aguilar Ayala
2. Marie Sylvianne Rabodoarivelo
3. Maxime R. Eveque-Mourroux
4. Albin AM Leding
5. Lindsay Sonnekalb
6. Ana Picó Marco
7. Nicolas Willand
8. Natalya Serbina
9. Ulrika SH Simonsson
10. Ainhoa Lucía
11. Santiago Ramón-García
12. ERA4TB consortium

Reviewed by preLights

Nonspecific membrane bilayer perturbations by ivermectin underlie SARS-CoV-2 in vitro activity

1. Richard T Eastman
2. Radda Rusinova
3. Karl F Herold
4. Xi-Ping Huang
5. Patricia Dranchak
6. Ty C Voss
7. Sandeep Rana
8. Jonathan H Shrimp
9. Alex D White
10. Hugh C Hemmings
11. Bryan L Roth
12. James Inglese
13. Olaf S Andersen
14. Jayme L Dahlin

Reviewed by Rapid Reviews Infectious Diseases

Mid-zone hepatocytes trade proliferation for survival via Atf4-Chop axis in early acute liver injury

1. Yaying Zhu
2. Chengxiang Deng
3. Bo Chen
4. Jia He
5. Yanan Liu
6. Cheng Peng
7. Zhao Shan

• Curated by eLife

  eLife Assessment

  This study addresses an important question in liver biology: how zonal hepatocytes balance survival and proliferation following injury; using spatial transcriptomics, mechanistic perturbations, and functional assays, the authors propose that a mid-zone Atf4-Chop axis to Btg2 program temporarily suppresses proliferation to promote survival during APAP-induced hepatotoxicity. The idea that distinct intrahepatic zones mount tailored stress responses is conceptually significant and has implications for regeneration and toxicology. The dataset is rich and the methodology modern, but several conclusions rely on assumptions about zonation under injury, limited injury models, and incomplete functional validation of the Atf4-Chop-Btg2 axis. With targeted revisions and additional experiments, the work has the potential to provide strong mechanistic insights into liver zonation and injury responses.

Reviewed by eLife