Evidence map›Paper›PMID 42229415›Full record

ArticleMolecular cell2026

Reductive death is averted by a conserved de novo lipogenic switch.

Fasih M Ahsan, Jen F Rotti, Armen I Yerevanian, Sinclair W Emans, Nicole L Stuhr, Jose A Aceves-Salvador, Wei Wang, Daniel J Baker, Dimitra Pouli, Owen S Skinner and 2 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular cell, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

12 authors.

Fasih M AhsanDepartment of Medicine, Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Biological and Biomedical Sciences, Division of Medical Sciences, Harvard Medical School, Boston, MA 02115, USA.
Jen F RottiDepartment of Medicine, Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Armen I YerevanianDepartment of Medicine, Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
Sinclair W EmansDepartment of Medicine, Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Biological and Biomedical Sciences, Division of Medical Sciences, Harvard Medical School, Boston, MA 02115, USA.
Nicole L StuhrDepartment of Medicine, Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Jose A Aceves-SalvadorProgram in Biological and Biomedical Sciences, Division of Medical Sciences, Harvard Medical School, Boston, MA 02115, USA.
Wei WangDepartment of Biochemistry and Cell Biology, Chobanian and Avedisian School of Medicine, Boston University, Boston, MA 02118, USA.
Daniel J BakerDepartment of Medicine, Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Dimitra PouliDepartment of Medicine, Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Pathology, Boston Children's Hospital, Boston, MA 02115, USA.
Owen S SkinnerDepartment of Chemistry and Chemical Biology, College of Science, Northeastern University, Boston, MA 02115, USA.
Michael D BlowerDepartment of Biochemistry and Cell Biology, Chobanian and Avedisian School of Medicine, Boston University, Boston, MA 02118, USA.
Alexander A SoukasDepartment of Medicine, Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: asoukas@mgh.harvard.edu.

Funding

NIA NIH HHS R01 AG058256NIA NIH HHS R01 AG069677
6 · The paper itself

Abstract

Biguanides, including metformin, the world's most prescribed oral hypoglycemic, extend health span and lifespan in vertebrates and invertebrates. Given the widespread use and apparent safety of metformin, it is assumed that its effects are not associated with toxicity, except when in marked excess. Here, we determine that accumulation of damaging reducing equivalents is an unanticipated toxicity associated with biguanides, defense against which requires post-transcriptional protection of de novo lipogenesis. We demonstrate that biguanide treatment during impaired lipogenesis drives NADPH toxicity, leading to catastrophic elevation of NADH/GSH reducing equivalents and accelerated death across metazoans. Multiple NADPH-generating interventions require de novo lipogenesis to prevent markedly shortened survival, indicating that this defense mechanism is broadly leveraged. We propose that fatty acid biosynthesis is a tunable rheostat that can minimize biguanide-induced reductive stress while maximizing its pro-longevity outcomes and can serve as an exploitable vulnerability in reductive stress-sensitive cancers.

Indexed as

BiguanidesCaenorhabditis elegansLipogenesisMetforminAnimalsCaenorhabditis elegans ProteinsFatty AcidsGlutathioneHypoglycemic AgentsLongevityNADNADPOxidation-ReductionPhenforminBiguanidesCaenorhabditis elegans ProteinsFatty AcidsGlutathioneHypoglycemic AgentsMetforminNADNADPPhenforminCaenorhabditis eleganscancerde novo lipogenesiseukaryotic initiation factor 3lifespanmetforminmRNA translationphenforminprotein synthesisreductive stress

Identifiers

PMID42229415
PMCPMC13386819

What Socratic holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.