Tissue-autonomous pharmacological direction: how target expression landscapes convert balanced compounds into tissue-selective agents.
Overview
- Chengdu University of Traditional Chinese Medicine, Chengdu, China
- King’s College London, London, United Kingdom
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
Abstract
Multi-target drugs frequently exhibit tissue-dependent pharmacological directions: the same compound may promote a biological process in one organ while driving its functional opposite in another. Tamoxifen antagonizes estrogen receptors in breast tissue yet activates them in the endometrium; non-selective NSAIDs reduce inflammation at injury sites while damaging the gastric mucosa. Each phenomenon has been explained by drug-specific mechanisms, but no unifying principle predicts when or why such direction reversal occurs. Here we propose tissue-autonomous pharmacological direction (TAPD): when a compound simultaneously engages two functionally opposing target classes, its net pharmacological direction in any tissue is determined primarily by which class is more abundantly expressed locally. We formalize this principle through the Tissue Direction Index (TDI), a dimensionless metric (0–1) integrating binding affinity with tissue-specific expression data from transcriptomic atlases. As proof of concept, we show that bridging metabolites from traditional Chinese botanical drugs with uniform molecular-level coagulation bias undergo substantial hemostatic direction shifts between gastrointestinal and brain tissue (4.6-fold Hemostatic Index change, driven predominantly by expression differences), with two metabolites achieving complete direction reversal. We then discuss how TAPD complements existing models of tissue-selective drug effects, including SERMs, NSAIDs, kinase inhibitors, and immunomodulators, and outline translational applications in drug repurposing, predictive toxicology, and patient-specific pharmacological prediction.
Reproduced under the paper's license (CC BY), from the paper cited above.
Code
The paper links to its data, not to its authors' code: see the Data section.
Tracing map
A tracing map links a paper to the code its authors published: this paper has none, so it has no map.
Data
Datasets cited
- geo:GSE16561, at NCBI GEO; found in “Data availability statement”
- zenodo:20765877, at Zenodo; found in “Data availability statement”
- zenodo:20765878, at Zenodo; found in DataCite
Other data links
- ncbi.nlm.nih.gov/
geo , NCBI; found in “Data availability statement”
Data availability statement
Publicly available datasets were analyzed in this study. The transcriptomic data are available from the GTEx Portal (GTEx v8; https://
Reproduced under the paper's license (CC BY), from the paper cited above.
Versions
The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.
Version 2, 28 September 2026
- Funding: added Ministry of Science and Technology of the People's Republic of China
Version 1, 27 September 2026: the first record
Recorded: type, language, journal, volume, pages, dates, 3 authors, 8 keywords, 41 references.
Cite
This paper
Chen, H., Chen, Q., & Wang, Y. (2026). Tissue-autonomous pharmacological direction: how target expression landscapes convert balanced compounds into tissue-selective agents. Frontiers in pharmacology, 17, 1870571. https://
BibTeX
@article{chen2026tissue,
author = {Chen, Huizhen and Chen, Qiu and Wang, Yanzhong},
title = {{Tissue-autonomous pharmacological direction: how target expression landscapes convert balanced compounds into tissue-selective agents}},
journal = {Frontiers in pharmacology},
year = {2026},
month = jun,
volume = {17},
pages = {1870571},
publisher = {Frontiers Media SA},
issn = {1663-9812},
doi = {10.3389/
url = {https://
pmid = {42453585},
pmcid = {PMC13365337}
}
RIS
TY - JOUR
AU - Chen, Huizhen
AU - Chen, Qiu
AU - Wang, Yanzhong
TI - Tissue-autonomous pharmacological direction: how target expression landscapes convert balanced compounds into tissue-selective agents
T2 - Frontiers in pharmacology
J2 - Front Pharmacol
PY - 2026
DA - 2026/
VL - 17
SP - 1870571
SN - 1663-9812
PB - Frontiers Media SA
DO - 10.3389/
UR - https://
LA - en
ER -
CSL-JSON
{
"id": "10.3389/
"type": "article-journal",
"title": "Tissue-autonomous pharmacological direction: how target expression landscapes convert balanced compounds into tissue-selective agents",
"container-title": "Frontiers in pharmacology",
"author": [
{
"family": "Chen",
"given": "Huizhen"
},
{
"family": "Chen",
"given": "Qiu"
},
{
"family": "Wang",
"given": "Yanzhong"
}
],
"container-title-short":
"volume": "17",
"page": "1870571",
"DOI": "10.3389/
"PMID": "42453585",
"PMCID": "PMC13365337",
"ISSN": "1663-9812",
"publisher": "Frontiers Media SA",
"URL": "https://
"language": "en",
"issued": {
"date-parts": [
[
2026,
6,
30
]
]
}
}
Similar papers
The papers with a page that share the most with this one: the tools found in their code, their categories, datasets, cited references and authors, the rarest counting most.
- [1] doi:10.1186/s12951-026-04551-7
- The role of AI-assisted drug repurposing in neurological disorders: a systematic review of validation strategies, challenges and opportunities.Journal: Journal of nanobiotechnologyIn common: NCBI GEO GSE16561, 1 reference
- [2] doi:10.3389/fmolb.2026.1844734
- Discovery and validation of programmed cell death-associated key biomarker genes in ischemic stroke via ssGSEA/
WGCNA and LASSO-SVM-RFE. Journal: Frontiers in molecular biosciencesIn common: NCBI GEO GSE16561 - [3] doi:10.1038/s44321-026-00473-x
- OTUB1 non-canonically inhibits TAB2 ubiquitination to govern microglia-mediated neuroinflammation.Journal: EMBO molecular medicineIn common: NCBI GEO GSE16561
- [4] doi:10.1002/jnr.70130
- Pantothenic Acid Protects Neurons After Ischemic Stroke by Targeting ID3 to Restore Action Potential Amplitude.Journal: Journal of neuroscience researchIn common: NCBI GEO GSE16561
- [5] doi:10.1007/s10571-026-01710-0
- The Role and Diagnostic Efficacy of the METTL14/
GADD45B m& lt;sup& gt;6& lt;/ sup& gt;A Methylation/ BDNF Regulatory Axis in Acute Ischemic Stroke. Journal: Cellular and molecular neurobiologyIn common: NCBI GEO GSE16561 - [6] doi:10.3390/biomedicines14050998 [code]
- Integrative Multi-Omics and Machine Learning Analysis Identifies Therapeutic Targets and Drug Repurposing Candidates for Alzheimer's Disease.Journal: BiomedicinesIn common: genetics / omics, 2 references
- [7] doi:10.1038/s41467-026-76676-0 [code]
- Determinants of functional burden pleiotropy and gene dosage responses across human traits.Journal: Nature communicationsIn common: genetics / omics, 2 references
- [8] doi:10.1016/j.cell.2026.05.047 [code]
- An emergent disease-associated motor neuron state precedes cell death in ALS.Journal: CellIn common: genetics / omics, 2 references
- [9] doi:10.1038/s42003-026-10380-z [code]
- Identification of moderate effect size genes in autism spectrum disorder through a novel gene pairing approach.Journal: Communications biologyIn common: genetics / omics, 2 references
- [10] doi:10.3390/ijms27114820
- Integrating Divergence-Based Proteomic Analysis and Directed Network Diffusion to Characterize Diagnosis-Anchored Molecular Variability at the Metabolic Syndrome-Migraine Interface.Journal: International journal of molecular sciencesIn common: genetics / omics, 2 references
Contribute
The authors of this paper can claim it, correct its record and validate its tracing map, and the maintainers of its code (its owner, or a public member of its organization) correct what it says of their repository; anyone signed in can ask for its removal. Every request goes to OSCR's own machine, which answers it; your account page follows them.
Sign in with ORCID to claim this paper as one of its authors, correct its record or validate its tracing map: when the paper's metadata lists your ORCID iD, you are recognized at once. Maintainers of its code: sign in with GitHub, then claim the repository on your account page.
Claim this paper
Correct its record
Say what each link of this record is, remove the ones that are not the paper's, add the ones that are missing. The correction becomes a new version of the record, in its Versions section.
Request its removal
To ask OSCR to remove this record, the copies of its authors' scripts or its tracing map, use the removal request page: signed in, you say who you are, what to remove and why, then review and confirm the request. Published rules decide every request (how).
Discussion, reproductions, activity
Discussion: questions and error reports about this paper and its code, from signed-in readers and its authors. It opens with sign-in.
Reproductions: reports from readers who ran the authors' code: what they reproduced, with which environment, commit and data. It opens with sign-in.
Activity: what happens around this paper: new versions of its record, its map's validation, discussions and reproductions. It opens with sign-in.