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Top novel candidate Hypothesis #37636 high quality

Auranofin → TDP-43 → ALS

Cross-domain hypothesis: Rheumatoid arthritis drug → ALS outcome

Figure 1. Hypothesis chain: Auranofin (inhibits) TDP-43 (associated with) ALS.
Partial evidence baseline
Outreach score
0.614
Evidence A → B
1
papers
Evidence B → C
29
papers
Direct A → C
0
papers

Evidence network

The full set of scientific papers supporting this hypothesis, visualized as a force-directed graph. Each gray node is one paper; hover for the extracted claim, click to open it on PubMed.

Figure 2. Evidence network for Auranofin → TDP-43 → ALS. Each gray node represents a scientific paper from the Robertium extraction. A→B edges show Auranofin → TDP-43 claims; B→C edges show TDP-43 → ALS claims. Hover for details, click a paper to open PubMed. Showing 28 unique B→C papers with extracted claims (metric reports 29 total works for this leg; difference is extraction artifact).
View as text list

A→B papers (1)

  • PMID 29396541 — TDP-43 self-interaction is modulated by redox-active compounds Auranofin, Chelerythrine and Riluzole (2018) · self-interaction conf 0.95

B→C papers (28)

  • PMID 41570741 — ALS-related proteinopathies: From TDP-43 to mitochondrial proteinopathies (2026) conf 0.80
  • PMID 41813136 — ALS and Huntington Disease: Unraveling the Connections between TDP-43 and Huntingtin (2026) · in 97% of ALS cases conf 0.95
  • PMID 41851044 — Reduced nuclear TDP-43 and cytoplasmic DLK1 as markers of motor neuron degeneration in amyotrophic lateral sclerosis (2026) · in upper and lower motor neurons conf 0.80
  • PMID 42013476 — Cryptic Splicing in ALS: From Driving Disease Progression to Unlocking Novel Therapeutics (2026) · amyotrophic lateral sclerosis conf 0.90
  • PMID 40619651 — TDP-43 Proteinopathies in ALS and FTLD: Mechanistic Insights andTherapeutic Approaches (2025) · in ALS and FTLD conf 0.90
  • PMID 41596063 — G-Quadruplexes Abet Neuronal Burnout in ALS and FTD (2025) · methionine alterations conf 0.80
  • PMID 38304795 — Validation of a newly developed immunoassay for TDP-43 in human plasma (2024) · human plasma conf 0.85
  • PMID 39727843 — Development of a Sensitive and Reliable Meso Scale Discovery-Based Electrochemiluminescence Immunoassay to Quantify TDP-43 in Human Biofluids (2024) · in blood of ALS patients compared to healthy controls conf 0.95
  • PMID 37527763 — A panel of TDP-43-regulated splicing events verifies loss of TDP-43 function in amyotrophic lateral sclerosis brain tissue (2023) · in brain tissue conf 0.90
  • PMID 35604654 — TDP-43 Accumulation Within Intramuscular Nerve Bundles of Patients With Amyotrophic Lateral Sclerosis (2022) · in nerve bundles as diagnostic biomarker conf 0.85
  • PMID 35652285 — TAR DNA-binding protein of 43 kDa (TDP-43) and amyotrophic lateral sclerosis (ALS): a promising therapeutic target (2022) · in 97% of ALS cases conf 0.90
  • PMID 36261296 — Finding Common Ground on the Site of Onset of Amyotrophic Lateral Sclerosis (2022) · in patients with ALS and FTD conf 0.60
  • PMID 33461623 — Spreading of TDP-43 pathology via pyramidal tract induces ALS-like phenotypes in TDP-43 transgenic mice (2021) · in patients with sporadic amyotrophic lateral sclerosis conf 0.80
  • PMID 34548609 — Age-related demethylation of the TDP-43 autoregulatory region in the human motor cortex (2021) · in motor cortex conf 0.95
  • PMID 34944548 — A Computational Approach to Investigate TDP-43 RNA-Recognition Motif 2 C-Terminal Fragments Aggregation in Amyotrophic Lateral Sclerosis (2021) · human conf 0.80
  • PMID 31529970 — Using Tetracysteine-Tagged TDP-43 with a Biarsenical Dye To Monitor Real-Time Trafficking in a Cell Model of Amyotrophic Lateral Sclerosis (2019) · as major constituent of proteinaceous inclusions conf 0.95
  • PMID 31722302 — [Neuropathology of Amyotrophic Lateral Sclerosis]. (2019) · in sporadic ALS conf 0.85
  • PMID 31722315 — [Immunotherapy Against Misfolded Proteins in ALS]. (2019) · in sporadic ALS conf 0.95
  • PMID 30072868 — Pathological Proteins Are Transported by Extracellular Vesicles of Sporadic Amyotrophic Lateral Sclerosis Patients (2018) · in microvesicles (MVs) from plasma of sporadic ALS patients compared to healthy controls conf 0.80
  • PMID 30442180 — Modeling hallmark pathology using motor neurons derived from the family and sporadic amyotrophic lateral sclerosis patient-specific iPS cells (2018) · in surviving motor neurons from ALS patients conf 0.90
  • PMID 28848086 — Cerebrospinal Fluid TAR DNA-Binding Protein 43 Combined with Tau Proteins as a Candidate Biomarker for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Spectrum Disorders (2017) · cerebrospinal fluid conf 0.90
  • PMID 28282387 — The essential and downstream common proteins of amyotrophic lateral sclerosis: A protein-protein interaction network analysis (2017) · in protein-protein interaction network analysis of classical ALS and ALS+FTD conf 0.70
  • PMID 26980269 — Mass spectrometric analysis of accumulated TDP-43 in amyotrophic lateral sclerosis brains (2016) · in amyotrophic lateral sclerosis brains conf 0.90
  • PMID 28000730 — An acridine derivative, [4,5-bis{(N-carboxy methyl imidazolium)methyl}acridine] dibromide, shows anti-TDP-43 aggregation effect in ALS disease models (2016) · in neuronal cells conf 0.95
  • PMID 27466204 — Enhancing survival motor neuron expression extends lifespan and attenuates neurodegeneration in mutant TDP-43 mice (2016) · in mutant TDP-43 mice model conf 0.85
  • PMID 26598621 — TDP-43 is intercellularly transmitted across axon terminals (2015) · in pathological aggregates conf 0.90
  • PMID 25637145 — Early detection of structural abnormalities and cytoplasmic accumulation of TDP-43 in tissue-engineered skins derived from ALS patients (2015) · in tissue-engineered skins derived from ALS patients conf 0.70
  • PMID 26689008 — [RNA processing TDP-43 protein has a main pathological role in FTLD and ALS]. (2015) · in Amyotrophic Lateral Sclerosis cases conf 0.90

Clinical trials

0 registered trials for Auranofin in ALS

Source: ClinicalTrials.gov

No registered trials found on ClinicalTrials.gov. This could indicate either an unexplored indication or a gap in registry coverage.

Search ClinicalTrials.gov →

Provenance trace

Full audit trail of how this hypothesis was generated: source papers, extracted claims, bridging logic, embedding model, and scoring. Every step is recorded and reproducible.

Provenance trace

Audit trail · Auranofin → TDP-43 → ALS

29 source papers, 31 extracted claims, scored by Swanson ABC chain.

Backfilled

Backfilled retroactively from DB state on 2026-05-13. The pipeline_run this row references was created by the backfill script, not by the actual generation orchestrator. Source papers, claims, scoring, and embedding config are recovered; generation-time metadata (exact git commit at gen time, host, exact command) is not recoverable.

1Source papers29
Filter
2Extracted claims31

Each row is one structured triple extracted by deepseek-v4-flash (prompt v1_2026_05_07, source: configured). Confidence is the LLM's self-rating.

  • auranofininhibitsTDP-43A→B
    "self-interaction"confidence 0.95· extraction run #29· claim #216269
  • auranofindecreasesTDP-43A→B
    "insoluble TDP-43 pool in N2a cells"confidence 0.90· extraction run #29· claim #216272
  • TDP-43associated_withALSB→C
    "in pathological aggregates"confidence 0.90· extraction run #15· claim #27501
  • TDP-43associated_withALSB→C
    "in amyotrophic lateral sclerosis brains"confidence 0.90· extraction run #15· claim #27772
  • TDP-43correlates_withALSB→C
    "in microvesicles (MVs) from plasma of sporadic ALS patients compared to healthy controls"confidence 0.80· extraction run #15· claim #27851
  • TDP-43associated_withALSB→C
    "in nerve bundles as diagnostic biomarker"confidence 0.85· extraction run #15· claim #29682
  • TDP-43associated_withALSB→C
    "in tissue-engineered skins derived from ALS patients"confidence 0.70· extraction run #15· claim #30619
  • TDP-43associated_withALSB→C
    "in neuronal cells"confidence 0.95· extraction run #15· claim #30752
  • TDP-43associated_withALSB→C
    "in surviving motor neurons from ALS patients"confidence 0.90· extraction run #15· claim #30797
  • TDP-43associated_withALSB→C
    "in patients with sporadic amyotrophic lateral sclerosis"confidence 0.80· extraction run #15· claim #31451
  • TDP-43causesALSB→C
    "in mutant TDP-43 mice model"confidence 0.85· extraction run #15· claim #32007
  • TDP-43associated_withALSB→C
    "in motor cortex"confidence 0.95· extraction run #15· claim #32407
  • TDP-43associated_withALSB→C
    "in brain tissue"confidence 0.90· extraction run #15· claim #33053
  • TDP-43associated_withALSB→C
    "as major constituent of proteinaceous inclusions"confidence 0.95· extraction run #15· claim #35515
  • TDP-43associated_withALSB→C
    "human"confidence 0.80· extraction run #15· claim #35872
  • TDP-43associated_withALSB→C
    "cerebrospinal fluid"confidence 0.90· extraction run #21· claim #98014
  • TDP-43associated_withALSB→C
    "in ALS and FTLD"confidence 0.90· extraction run #21· claim #99137
  • TDP-43associated_withALSB→C
    "in protein-protein interaction network analysis of classical ALS and ALS+FTD"confidence 0.70· extraction run #21· claim #99608
  • TDP-43associated_withALSB→C
    "in 97% of ALS cases"confidence 0.90· extraction run #21· claim #100211
  • TDP-43associated_withALSB→C
    "initiation and progression of ALS"confidence 0.70· extraction run #21· claim #100212
  • TDP-43associated_withALSB→C
    "human plasma"confidence 0.85· extraction run #21· claim #100239
  • TDP-43associated_withALSB→C
    "in sporadic ALS"confidence 0.85· extraction run #21· claim #101035
  • TDP-43causesALSB→C
    "in sporadic ALS"confidence 0.95· extraction run #21· claim #101095
  • TDP-43associated_withALSB→C
    "in patients with ALS and FTD"confidence 0.60· extraction run #21· claim #101653
  • TDP-43associated_withALSB→C
    "in Amyotrophic Lateral Sclerosis cases"confidence 0.90· extraction run #21· claim #101702
  • TDP-43associated_withALSB→C
    "in blood of ALS patients compared to healthy controls"polarity: negativeconfidence 0.95· extraction run #21· claim #101940
  • TDP-43associated_withALSB→C
    "methionine alterations"confidence 0.80· extraction run #21· claim #102745
  • TDP-43associated_withALSB→C
    confidence 0.80· extraction run #21· claim #102909
  • TDP-43associated_withALSB→C
    "in 97% of ALS cases"confidence 0.95· extraction run #21· claim #103326
  • TDP-43associated_withALSB→C
    "in upper and lower motor neurons"confidence 0.80· extraction run #21· claim #103437
  • TDP-43associated_withALSB→C
    "amyotrophic lateral sclerosis"confidence 0.90· extraction run #21· claim #103773
3Bridging logicSwanson ABC
Drug
Auranofin
inhibits
→
1 paper
Mediator
TDP-43
associated_with
→
29 papers
Outcome
ALS
edge_support_log_ab
log(ab + 1) = 0.693
edge_support_log_bc
log(bc + 1) = 3.401
novelty_factor
1.000 (no direct drug→outcome evidence — full novelty)
direct_a_to_c_count
0
4Embedding modelbge-m3

Embeddings are used at the L1 filtering stage to prune off-topic abstracts before claim extraction. They do not directly score the hypothesis.

model
bge-m3
dim
1024
max_length
8192 tokens
similarity_scores
No per-hypothesis cosine scores stored.
5Final scoringhigh · 0.614
method
swanson_abc_log_evidence_with_novelty_penalty
formula
score = min((log(ab+1) + log(bc+1)) * novelty / 10, 1.0); novelty = 1.0 if direct==0 else 0.7 / (direct+1)
raw score
0.4094
outreach score
0.6142
quality tier
high
Pipeline version
9996ffa
Pipeline run
id 4 · uuid eb8b7730…
Pipeline command
scripts/backfill_provenance_v2.py:v2_2026_05_12
Pipeline status
completed
Generated
2026-05-12 21:43:40 UTC
Schema version
1.0
Download full provenance JSON

Horizontal exploration

Similar hypotheses

Closest 8 of 1,618 hypotheses, ranked by hybrid score (50% bge-m3 embedding cosine · 40% drug/mediator/outcome overlap · 10% shared evidence papers).

  1. Alternative drug0.88
    chelerythrine→TDP-43→ALS

    Different drug, same disease outcome

    ALShigh
  2. Alternative drug0.87
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    Different drug, same disease outcome

    ALShigh★ case study
  3. New indication0.82
    Auranofin→TDP-43→FTLD

    Same drug + same mediator, different disease

    ALShigh
  4. New indication0.80
    Auranofin→TDP-43→neuronal dysfunction

    Same drug + same mediator, different disease

    ALSmid
  5. New indication0.79
    Auranofin→TDP-43→neurodegeneration

    Same drug + same mediator, different disease

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Show 3 more
  1. Cross-indication0.79
    Auranofin→Nrf2→antioxidant defense

    Same drug, different disease — potential alternate indication

    ALShigh
  2. New indication0.79
    Auranofin→TDP-43→Alzheimer's disease

    Same drug + same mediator, different disease

    ALSmid
  3. Cross-indication0.78
    Auranofin→GSK-3β→tau hyperphosphorylation

    Same drug, different disease — potential alternate indication

    Alzheimerhigh

The drug — Auranofin

Source domain: Rheumatoid arthritis · entity type: drug

View all hypotheses for Auranofin →

The mediator — TDP-43

Entity type: protein

The outcome — ALS

Target domain: ALS · entity type: disease

Evidence

Limited evidence base in our current extraction. Treat this hypothesis as a starting point for further literature review, not a settled conclusion.

A → B evidence: Auranofin inhibits TDP-43

  • PMID 29396541 TDP-43 self-interaction is modulated by redox-active compounds Auranofin, Chelerythrine and Riluzole (2018)

B → C evidence: TDP-43 associated with ALS

  • PMID 41570741 ALS-related proteinopathies: From TDP-43 to mitochondrial proteinopathies (2026)
  • PMID 41813136 ALS and Huntington Disease: Unraveling the Connections between TDP-43 and Huntingtin (2026)
  • PMID 41851044 Reduced nuclear TDP-43 and cytoplasmic DLK1 as markers of motor neuron degeneration in amyotrophic lateral sclerosis (2026)
  • PMID 42013476 Cryptic Splicing in ALS: From Driving Disease Progression to Unlocking Novel Therapeutics (2026)
  • PMID 40619651 TDP-43 Proteinopathies in ALS and FTLD: Mechanistic Insights andTherapeutic Approaches (2025)
  • PMID 41596063 G-Quadruplexes Abet Neuronal Burnout in ALS and FTD (2025)
  • PMID 38304795 Validation of a newly developed immunoassay for TDP-43 in human plasma (2024)
  • PMID 39727843 Development of a Sensitive and Reliable Meso Scale Discovery-Based Electrochemiluminescence Immunoassay to Quantify TDP-43 in Human Biofluids (2024)
  • PMID 37527763 A panel of TDP-43-regulated splicing events verifies loss of TDP-43 function in amyotrophic lateral sclerosis brain tissue (2023)
  • PMID 35604654 TDP-43 Accumulation Within Intramuscular Nerve Bundles of Patients With Amyotrophic Lateral Sclerosis (2022)
  • PMID 35652285 TAR DNA-binding protein of 43 kDa (TDP-43) and amyotrophic lateral sclerosis (ALS): a promising therapeutic target (2022)
  • PMID 36261296 Finding Common Ground on the Site of Onset of Amyotrophic Lateral Sclerosis (2022)
  • PMID 33461623 Spreading of TDP-43 pathology via pyramidal tract induces ALS-like phenotypes in TDP-43 transgenic mice (2021)
  • PMID 34548609 Age-related demethylation of the TDP-43 autoregulatory region in the human motor cortex (2021)
  • PMID 34944548 A Computational Approach to Investigate TDP-43 RNA-Recognition Motif 2 C-Terminal Fragments Aggregation in Amyotrophic Lateral Sclerosis (2021)
  • PMID 31529970 Using Tetracysteine-Tagged TDP-43 with a Biarsenical Dye To Monitor Real-Time Trafficking in a Cell Model of Amyotrophic Lateral Sclerosis (2019)
  • PMID 31722302 [Neuropathology of Amyotrophic Lateral Sclerosis]. (2019)
  • PMID 31722315 [Immunotherapy Against Misfolded Proteins in ALS]. (2019)
  • PMID 30072868 Pathological Proteins Are Transported by Extracellular Vesicles of Sporadic Amyotrophic Lateral Sclerosis Patients (2018)
  • PMID 30442180 Modeling hallmark pathology using motor neurons derived from the family and sporadic amyotrophic lateral sclerosis patient-specific iPS cells (2018)
  • PMID 28848086 Cerebrospinal Fluid TAR DNA-Binding Protein 43 Combined with Tau Proteins as a Candidate Biomarker for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Spectrum Disorders (2017)
  • PMID 28282387 The essential and downstream common proteins of amyotrophic lateral sclerosis: A protein-protein interaction network analysis (2017)
  • PMID 26980269 Mass spectrometric analysis of accumulated TDP-43 in amyotrophic lateral sclerosis brains (2016)
  • PMID 28000730 An acridine derivative, [4,5-bis{(N-carboxy methyl imidazolium)methyl}acridine] dibromide, shows anti-TDP-43 aggregation effect in ALS disease models (2016)
  • PMID 27466204 Enhancing survival motor neuron expression extends lifespan and attenuates neurodegeneration in mutant TDP-43 mice (2016)
  • PMID 26598621 TDP-43 is intercellularly transmitted across axon terminals (2015)
  • PMID 25637145 Early detection of structural abnormalities and cytoplasmic accumulation of TDP-43 in tissue-engineered skins derived from ALS patients (2015)
  • PMID 26689008 [RNA processing TDP-43 protein has a main pathological role in FTLD and ALS]. (2015)

References

All PMID-linked papers cited in the evidence network above, deduplicated and sorted by publication year.

  1. PMID 41570741 ALS-related proteinopathies: From TDP-43 to mitochondrial proteinopathies (2026) B→C
  2. PMID 41813136 ALS and Huntington Disease: Unraveling the Connections between TDP-43 and Huntingtin (2026) B→C
  3. PMID 41851044 Reduced nuclear TDP-43 and cytoplasmic DLK1 as markers of motor neuron degeneration in amyotrophic lateral sclerosis (2026) B→C
  4. PMID 42013476 Cryptic Splicing in ALS: From Driving Disease Progression to Unlocking Novel Therapeutics (2026) B→C
  5. PMID 40619651 TDP-43 Proteinopathies in ALS and FTLD: Mechanistic Insights andTherapeutic Approaches (2025) B→C
  6. PMID 41596063 G-Quadruplexes Abet Neuronal Burnout in ALS and FTD (2025) B→C
  7. PMID 38304795 Validation of a newly developed immunoassay for TDP-43 in human plasma (2024) B→C
  8. PMID 39727843 Development of a Sensitive and Reliable Meso Scale Discovery-Based Electrochemiluminescence Immunoassay to Quantify TDP-43 in Human Biofluids (2024) B→C
  9. PMID 37527763 A panel of TDP-43-regulated splicing events verifies loss of TDP-43 function in amyotrophic lateral sclerosis brain tissue (2023) B→C
  10. PMID 35604654 TDP-43 Accumulation Within Intramuscular Nerve Bundles of Patients With Amyotrophic Lateral Sclerosis (2022) B→C
  11. PMID 35652285 TAR DNA-binding protein of 43 kDa (TDP-43) and amyotrophic lateral sclerosis (ALS): a promising therapeutic target (2022) B→C
  12. PMID 36261296 Finding Common Ground on the Site of Onset of Amyotrophic Lateral Sclerosis (2022) B→C
  13. PMID 33461623 Spreading of TDP-43 pathology via pyramidal tract induces ALS-like phenotypes in TDP-43 transgenic mice (2021) B→C
  14. PMID 34548609 Age-related demethylation of the TDP-43 autoregulatory region in the human motor cortex (2021) B→C
  15. PMID 34944548 A Computational Approach to Investigate TDP-43 RNA-Recognition Motif 2 C-Terminal Fragments Aggregation in Amyotrophic Lateral Sclerosis (2021) B→C
  16. PMID 31529970 Using Tetracysteine-Tagged TDP-43 with a Biarsenical Dye To Monitor Real-Time Trafficking in a Cell Model of Amyotrophic Lateral Sclerosis (2019) B→C
  17. PMID 31722302 [Neuropathology of Amyotrophic Lateral Sclerosis]. (2019) B→C
  18. PMID 31722315 [Immunotherapy Against Misfolded Proteins in ALS]. (2019) B→C
  19. PMID 29396541 TDP-43 self-interaction is modulated by redox-active compounds Auranofin, Chelerythrine and Riluzole (2018) A→B
  20. PMID 30072868 Pathological Proteins Are Transported by Extracellular Vesicles of Sporadic Amyotrophic Lateral Sclerosis Patients (2018) B→C
  21. PMID 30442180 Modeling hallmark pathology using motor neurons derived from the family and sporadic amyotrophic lateral sclerosis patient-specific iPS cells (2018) B→C
  22. PMID 28848086 Cerebrospinal Fluid TAR DNA-Binding Protein 43 Combined with Tau Proteins as a Candidate Biomarker for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Spectrum Disorders (2017) B→C
  23. PMID 28282387 The essential and downstream common proteins of amyotrophic lateral sclerosis: A protein-protein interaction network analysis (2017) B→C
  24. PMID 26980269 Mass spectrometric analysis of accumulated TDP-43 in amyotrophic lateral sclerosis brains (2016) B→C
  25. PMID 28000730 An acridine derivative, [4,5-bis{(N-carboxy methyl imidazolium)methyl}acridine] dibromide, shows anti-TDP-43 aggregation effect in ALS disease models (2016) B→C
  26. PMID 27466204 Enhancing survival motor neuron expression extends lifespan and attenuates neurodegeneration in mutant TDP-43 mice (2016) B→C
  27. PMID 26598621 TDP-43 is intercellularly transmitted across axon terminals (2015) B→C
  28. PMID 25637145 Early detection of structural abnormalities and cytoplasmic accumulation of TDP-43 in tissue-engineered skins derived from ALS patients (2015) B→C
  29. PMID 26689008 [RNA processing TDP-43 protein has a main pathological role in FTLD and ALS]. (2015) B→C

Limitations & disclaimer

This hypothesis was generated algorithmically through cross-domain literature analysis and has not been experimentally validated. Treat it as a starting point for further investigation, not a therapeutic recommendation. For established knowledge about each entity, refer to the authoritative sources linked above (Wikipedia, DrugBank, UniProt, MeSH).

Related hypotheses

Other hypotheses in the catalog sharing the same drug or mediator.

shared mediator
curcumin → TDP-43 → ALS
score 0.614 View in catalog →
shared mediator
chelerythrine → TDP-43 → ALS
score 0.409 View in catalog →
shared drug
Auranofin → Nrf2 → chemoresistance
score 0.406 View in catalog →
How was this hypothesis generated? Read about Robertium's Swanson ABC discovery method View raw data in catalog Open hypothesis #37636 with full evidence and metadata