---
title: "Bile Acid–Mitochondria Axis: Mechanisms, Disease Links, and Therapeutic Targets"
id: "pubmed-42668075"
canonical_url: "https://medichelpline.com/clinical-feed/pubmed-42668075"
content_type: "clinical_feed_article"
specialty: "Critical Care"
source_name: "PubMed / NCBI"
source_url: "https://pubmed.ncbi.nlm.nih.gov/42668075/"
doi: "10.1016/j.phrs.2026.108415"
published_at: "2026-08-30T00:00:00.000Z"
evidence_level: "Journal Article"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Bile Acid–Mitochondria Axis: Mechanisms, Disease Links, and Therapeutic Targets
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/pubmed-42668075
- **Specialty:** [Critical Care](https://medichelpline.com/clinical-feed/critical-care.md)
- **Primary Source:** PubMed / NCBI
- **Source URL:** [Original Journal Publication](https://pubmed.ncbi.nlm.nih.gov/42668075/)
- **DOI:** [10.1016/j.phrs.2026.108415](https://doi.org/10.1016%2Fj.phrs.2026.108415)
- **Published At:** 2026-08-30T00:00:00.000Z
- **Evidence Rating:** Journal Article
## Executive GIST (TL;DR)
- Bile acids, derived from cholesterol, form a regulatory network with **mitochondrial quality control (MQC)** that influences biogenesis, dynamics (fission/fusion), selective autophagy (mitophagy), and redox balance. - The nuclear receptor **FXR** and membrane receptor **TGR5** are central mediators: TGR5 activates PGC‑1α‑driven mitochondrial biogenesis via the **cAMP–PKA–CREB** pathway and modulates fission and calcium handling through **PKCδ/Drp1** and **GRP75–MAMs** pathways. - **FXR** controls fatty acid oxidation, antioxidant defenses, and apoptotic signaling through transcriptional reprogramming and epigenetic mechanisms, and can restore **PINK1/Parkin** mitophagy while suppressing **NLRP3** inflammasome activation in alcoholic liver disease. - Noncanonical receptors including **S1PR2**, **VDR**, and **PXR** also contribute to regulation of mitochondrial dynamics and autophagy within this bile acid–mitochondria axis. - Dysregulation of the bile acid–mitochondria network is associated with metabolic dysfunction‑associated fatty liver disease (MAFLD), diabetic retinopathy, pancreatic β‑cell injury, alcoholic liver disease, and sepsis‑induced immunoparalysis. - Small‑molecule agonists targeting these receptors (for example, **INT‑777**, **INT‑767**, and **Fexaramine**) have shown the ability to restore mitochondrial function and reduce tissue damage in preclinical animal models. - The authors recommend future research using multi‑omics and structural biology to resolve receptor crosstalk, concentration‑dependent bidirectional effects, and to develop tissue‑selective modulators to advance clinical translation.
## Clinical Analysis & Structured Key Points
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Online ahead of print. # Decoding the Bile Acid-Mitochondria Axis: Implications for Disease Management and Therapeutic Opportunities [Xueru Jia](https://pubmed.ncbi.nlm.nih.gov/?term=Jia+X&cauthor_id=42668075)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42668075/#full-view-affiliation-1 "School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, 102488, Beijing, China."), [Zehan Zhang](https://pubmed.ncbi.nlm.nih.gov/?term=Zhang+Z&cauthor_id=42668075)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42668075/#full-view-affiliation-1 "School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, 102488, Beijing, China."), [Xiaoyu Lin](https://pubmed.ncbi.nlm.nih.gov/?term=Lin+X&cauthor_id=42668075)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42668075/#full-view-affiliation-1 "School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, 102488, Beijing, China."), [Xiangyue Dong](https://pubmed.ncbi.nlm.nih.gov/?term=Dong+X&cauthor_id=42668075)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42668075/#full-view-affiliation-1 "School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, 102488, Beijing, China."), [Ruixue Chen](https://pubmed.ncbi.nlm.nih.gov/?term=Chen+R&cauthor_id=42668075)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42668075/#full-view-affiliation-1 "School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, 102488, Beijing, China."), [Nan Liang](https://pubmed.ncbi.nlm.nih.gov/?term=Liang+N&cauthor_id=42668075)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42668075/#full-view-affiliation-2 "School of Chinese Materia Medica, Beijing University of Chinese Medicine, 102488, Beijing, China."), [He Ding](https://pubmed.ncbi.nlm.nih.gov/?term=Ding+H&cauthor_id=42668075)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42668075/#full-view-affiliation-1 "School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, 102488, Beijing, China."), [Feng Li](https://pubmed.ncbi.nlm.nih.gov/?term=Li+F&cauthor_id=42668075)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42668075/#full-view-affiliation-3 "School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, 102488, Beijing, China. Electronic address: lifeng_bucm0610@126.com.") Affiliations Expand ### Affiliations * 1 School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, 102488, Beijing, China. * 2 School of Chinese Materia Medica, Beijing University of Chinese Medicine, 102488, Beijing, China. * 3 School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, 102488, Beijing, China. Electronic address: lifeng_bucm0610@126.com. * PMID: **42668075** * DOI: [ 10.1016/j.phrs.2026.108415 ](https://doi.org/10.1016/j.phrs.2026.108415) Item in Clipboard Review # Decoding the Bile Acid-Mitochondria Axis: Implications for Disease Management and Therapeutic Opportunities Xueru Jia et al. Pharmacol Res. 2026. Show details Display options Display options Format Abstract PubMed PMID Pharmacol Res Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Pharmacol+Res%22%5Bjour%5D&sort=date&sort_order=desc) * [ Search in NLM Catalog ](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22Pharmacol+Res%22%5BTitle+Abbreviation%5D) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42668075/) . 2026 Aug 30:108415. doi: 10.1016/j.phrs.2026.108415. Online ahead of print. ### Authors [Xueru Jia](https://pubmed.ncbi.nlm.nih.gov/?term=Jia+X&cauthor_id=42668075)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42668075/#short-view-affiliation-1 "School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, 102488, Beijing, China."), [Zehan Zhang](https://pubmed.ncbi.nlm.nih.gov/?term=Zhang+Z&cauthor_id=42668075)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42668075/#short-view-affiliation-1 "School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, 102488, Beijing, China."), [Xiaoyu Lin](https://pubmed.ncbi.nlm.nih.gov/?term=Lin+X&cauthor_id=42668075)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42668075/#short-view-affiliation-1 "School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, 102488, Beijing, China."), [Xiangyue Dong](https://pubmed.ncbi.nlm.nih.gov/?term=Dong+X&cauthor_id=42668075)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42668075/#short-view-affiliation-1 "School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, 102488, Beijing, China."), [Ruixue Chen](https://pubmed.ncbi.nlm.nih.gov/?term=Chen+R&cauthor_id=42668075)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42668075/#short-view-affiliation-1 "School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, 102488, Beijing, China."), [Nan Liang](https://pubmed.ncbi.nlm.nih.gov/?term=Liang+N&cauthor_id=42668075)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42668075/#short-view-affiliation-2 "School of Chinese Materia Medica, Beijing University of Chinese Medicine, 102488, Beijing, China."), [He Ding](https://pubmed.ncbi.nlm.nih.gov/?term=Ding+H&cauthor_id=42668075)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42668075/#short-view-affiliation-1 "School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, 102488, Beijing, China."), [Feng Li](https://pubmed.ncbi.nlm.nih.gov/?term=Li+F&cauthor_id=42668075)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42668075/#short-view-affiliation-3 "School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, 102488, Beijing, China. Electronic address: lifeng_bucm0610@126.com.") ### Affiliations * 1 School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, 102488, Beijing, China. * 2 School of Chinese Materia Medica, Beijing University of Chinese Medicine, 102488, Beijing, China. * 3 School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, 102488, Beijing, China. Electronic address: lifeng_bucm0610@126.com. * PMID: **42668075** * DOI: [ 10.1016/j.phrs.2026.108415 ](https://doi.org/10.1016/j.phrs.2026.108415) Item in Clipboard Cite Display options Display options Format Abstract PubMed PMID ## Abstract Bile acids, as cholesterol metabolites, orchestrate a regulatory network with mitochondrial quality control (MQC) through nuclear receptor FXR, membrane receptor TGR5, and other signaling molecules, modulating mitochondrial biogenesis, dynamic equilibrium, selective autophagy, and redox homeostasis. TGR5 promotes PGC-1α-mediated mitochondrial biogenesis via the cAMP-PKA-CREB pathway, while concurrently regulating mitochondrial fission and calcium homeostasis through the PKCδ/Drp1 and GRP75-MAMs pathways. FXR, acting through transcriptional reprogramming and epigenetic mechanisms, governs fatty acid oxidation, antioxidant defense, and apoptotic pathways, and has been shown to restore PINK1/Parkin-dependent autophagy and suppress NLRP3 inflammasome activation in alcoholic liver disease. Noncanonical receptors, including S1PR2, VDR, and PXR, also participate in the regulation of mitochondrial dynamics and autophagy. Dysregulation of this network is closely associated with metabolic dysfunction-associated fatty liver disease, diabetic retinopathy, pancreatic β-cells injury, alcoholic liver disease, and sepsis-induced immunoparalysis. Agonists targeting the aforementioned receptors, such as INT-777, INT-767, and Fexaramine, have demonstrated the capacity to restore mitochondrial function and alleviate tissue damage in animal models. Future investigations should employ multi-omics and structural biology approaches to elucidate receptor crosstalk and concentration-dependent bidirectional effects, and to develop tissue-selective modulators, thereby facilitating clinical translation. **Keywords:** FXR; TGR5; bile acids; metabolic diseases; mitochondrial dynamics; mitochondrial quality control; mitophagy. Copyright © 2026. Published by Elsevier Ltd. [PubMed Disclaimer](https://pubmed.ncbi.nlm.nih.gov/disclaimer/) ## Conflict of interest statement Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Xueru Jia reports was provided by Beijing University of Chinese Medicine. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. 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