Evidence map›Paper›PMID 41659618›Full record

ArticlebioRxiv : the preprint server for biology2026

Mechanistic Language Modeling and Oxygenated 3D Screening Reveal Berberine and Enzalutamide Synergy in Resistant Prostate Cancer.

Chih-Hui Lo, Katie Shi, Lina Kafadarian, Alexandra Bermudez, Johnny Diaz, Liam Edwards, Yunqi Hong, Ziyi Chen, Hyeonji Hwang, Weihong Yan and 6 more

Abstract readPreprint
PubMed Full text at PMC Publisher
In one paragraph

Article in bioRxiv : the preprint server for biology, 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

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

16 authors.

Chih-Hui LoBioengineering Department, University of California Los Angeles, Los Angeles, CA, USA.
Katie ShiBioengineering Department, University of California Los Angeles, Los Angeles, CA, USA.
Lina KafadarianBioengineering Department, University of California Los Angeles, Los Angeles, CA, USA.
Alexandra BermudezBioengineering Department, University of California Los Angeles, Los Angeles, CA, USA.
Johnny DiazDepartment of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA.
Liam EdwardsMechanical and Aerospace Engineering Department, University of California Los Angeles, Los Angeles, CA, USA.
Yunqi HongComputer Science Department, University of California Los Angeles, Los Angeles, CA, USA.
Ziyi ChenDepartment of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA.
Hyeonji HwangDepartment of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA.
Weihong YanDepartment of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA.
Alan LevinsonBioengineering Department, University of California Los Angeles, Los Angeles, CA, USA.
Robert DamoiseauxBioengineering Department, University of California Los Angeles, Los Angeles, CA, USA.
Cho-Jui HsiehComputer Science Department, University of California Los Angeles, Los Angeles, CA, USA.
Tanya StoyanovaDepartment of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA.
Andrew S GoldsteinDepartment of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA.
Neil Y C LinBioengineering Department, University of California Los Angeles, Los Angeles, CA, USA.

Funding

UCLA SPORE IN PROSTATE CANCERP50CA092131 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI REITER, ROBERT E · 2002 to 2023
$42.6M
Testing ATAD2 as a new therapeutic target for advanced prostate cancerR01CA287669 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI Tanya I Stoyanova · 2024 to 2026
$2.8M
Elucidating the Role of Trop2 in Prostate CancerR37CA240822 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI Tanya I Stoyanova · 2020 to 2026
$2.5M
AI-Informed Signaling Factor Design for In Vitro Rejuvenating Mesenchymal Stromal CellsR35GM146735 · NIGMS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI Neil Lin · 2022 to 2026
$2.3M
Delineate the Role of GSTP1 in Advanced Prostate CancerR01CA274978 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI Tanya I Stoyanova · 2023 to 2026
$1.8M
NCI NIH HHS P50 CA092131NCI NIH HHS R01 CA274978NCI NIH HHS R01 CA287669NCI NIH HHS R37 CA240822NIGMS NIH HHS R35 GM146735
6 · The paper itself

Abstract

Resistance to androgen receptor inhibitors remains a primary challenge in prostate cancer treatment, yet identifying synergistic co-therapies is hindered by immense combinatorial search spaces and the limited interpretability of predictive computation models. Here, we developed an integrated discovery-validation axis coupling knowledge-augmented large language models with oxygen-supplemented 3D spheroid assays. By leveraging inherent model stochasticity, our framework measures the degree of consensus across independent predictions to establish a formal metric for predictive accuracy. This principle enables high-throughput assessment of complex signaling crosstalk, yielding mechanistic rationales for all predictions and defining a high-confidence zone that minimizes experimental attrition. Utilizing this approach to screen 3,592 natural products, we identified a previously unrecognized synergy between berberine and enzalutamide that re-sensitizes resistant cells. Validation confirms that berberine perturbs the PI3K/AKT/mTOR and AMPK axes, a finding consistent with the mechanistic rationales computationally derived by the framework. Integrating interpretable AI with physiologically relevant 3D screening provides a scalable methodology for the rational discovery of synergistic therapies.

Identifiers

PMID41659618
PMCPMC12874029

What OpenQuestion holds

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LicenceCC BY
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Registered trials

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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 OpenQuestion graph.