Hepatic long non-coding RNA SNHG9 links gut microbiota to liver protection in acetaminophen-induced liver injury by activating MAS receptor-mediated autophagy through an IMP2-MYC-MAS1 signaling axis, and is modulated by the gut microbiota metabolite 2-hydroxy 2-methylbutyric acid (HMB).
Key Findings
Results
Hepatic SNHG9 is a long non-coding RNA that is upregulated in response to APAP-induced liver injury and confers hepatoprotection.
SNHG9 upregulation protects against hepatotoxicity caused by acetaminophen (APAP), a leading cause of drug-induced liver injury and acute liver failure.
Hepatic SNHG9 was identified as a key mediator linking gut microbiota signals to liver stress responses.
The protective role of SNHG9 was established as a 'previously unrecognized' component of hepatic stress response regulation.
Results
SNHG9 protects the liver by activating MAS, a G protein-coupled receptor that enhances autophagy-mediated clearance of cellular damage.
MAS (encoded by MAS1 gene) is a G protein-coupled receptor whose activation facilitates clearance of cellular damage via enhanced autophagy.
Upregulation of hepatic SNHG9 leads to increased MAS expression, connecting the lncRNA to a receptor-mediated protective pathway.
Enhanced autophagy downstream of MAS activation is identified as the mechanistic basis for cellular protection during hepatotoxic stress.
Results
SNHG9 mechanistically suppresses MYC translation by binding to IMP2 and enhancing its interaction with MYC mRNA.
SNHG9 physically binds to insulin-like growth factor 2 mRNA-binding protein 2 (IMP2).
This binding enhances IMP2's interaction with MYC mRNA, leading to suppression of MYC translation.
MYC functions as a transcriptional repressor of the MAS1 gene, so its suppression results in upregulated MAS expression.
The pathway constitutes a SNHG9 → IMP2 → MYC suppression → MAS1 de-repression signaling cascade.
Results
Hepatic SNHG9 expression is modulated by the gut microbiota, particularly through the metabolite 2-hydroxy 2-methylbutyric acid (HMB).
The gut microbiota was identified as a regulator of hepatic SNHG9 expression levels.
HMB (2-hydroxy 2-methylbutyric acid) is a specific gut microbiota-derived metabolite that modulates SNHG9 expression in the liver.
This represents a gut-liver axis mechanism whereby microbial metabolites influence hepatic gene expression to regulate stress responses.
Results
Supplementation with HMB or HMB-producing microbes robustly induces hepatic SNHG9 expression and attenuates APAP-induced liver injury.
Direct supplementation with HMB was sufficient to induce hepatic SNHG9 expression.
Administration of HMB-producing microbes also induced hepatic SNHG9 expression.
Both HMB supplementation and HMB-producing microbe supplementation 'robustly' attenuated APAP-induced liver injury.
These findings suggest that manipulating gut microbiota composition or its metabolite output could be a therapeutic strategy for DILI.
Discussion
The study identifies a previously unrecognized gut-liver axis operating through microbial metabolite → hepatic lncRNA → autophagy signaling.
The axis connects gut microbiota (via HMB production) to hepatic SNHG9 lncRNA expression, then to IMP2-MYC-MAS1 signaling and autophagy.
This pathway provides mechanistic insight into how gut microbiota regulate hepatic stress responses during drug-induced liver injury.
The authors describe this as 'a previously unrecognized gut-liver axis.'
Background
Drug-induced liver injury (DILI) is identified as a leading cause of acute liver failure with significant public health burden, and gut microbiota are an understudied environmental factor in its progression.
DILI is described as 'a leading cause of acute liver failure, posing a significant public health burden.'
Emerging evidence underscores gut microbiota as 'a critical environmental factor that profoundly influences liver function and DILI progression.'
The underlying mechanisms linking gut microbiota to DILI progression were described as 'poorly understood' prior to this study.
Acetaminophen (APAP) was used as the model compound for DILI investigation.
What This Means
This research suggests that the bacteria living in our gut play an important role in protecting the liver from drug damage, particularly from acetaminophen (Tylenol) overdose — one of the most common causes of acute liver failure. Scientists discovered a previously unknown chain of molecular events: certain gut bacteria produce a chemical called HMB (2-hydroxy 2-methylbutyric acid), which travels to the liver and switches on a gene called SNHG9. When SNHG9 is active, it triggers a cascade of molecular signals that ultimately activates a protein receptor called MAS, which helps liver cells clean up damage through a process called autophagy (cellular self-cleaning). When this pathway is working well, the liver is better protected against toxic drug doses.
The molecular details of how this works were carefully mapped: SNHG9 (which belongs to a class of molecules called long non-coding RNAs) grabs onto a protein called IMP2, which then prevents the production of another protein called MYC. Since MYC normally acts as a brake on the MAS receptor gene, reducing MYC allows more MAS to be made, which in turn boosts the liver's self-protective autophagy response. This research suggests that the composition of a person's gut microbiome — which varies between individuals — could help explain why some people are more susceptible to liver damage from medications than others.
Practically, this study suggests that supplementing with HMB directly, or with bacteria that produce HMB, could potentially help protect the liver against drug-induced injury. This opens possible avenues for probiotic or metabolite-based interventions to reduce the risk or severity of drug-induced liver injury, which is a serious and sometimes fatal condition with limited treatment options beyond liver transplant.
Bao W, Hang B, Zeng D, Mao J, Pan L, Wang L, et al.. (2026). Hepatic SNHG9 links gut microbiota to liver protection in drug-induced liver injury.. Nature communications. https://doi.org/10.1038/s41467-026-73309-4