How a Liver Protein Decides Between Repair and Ruin
The human liver is a remarkable organ with an incredible capacity for self-regeneration. Yet, when overwhelmed by toxins, drugs, or disease, this regenerative power can falter, leading to irreversible damage. For years, scientists have meticulously mapped the liver's response to injury, focusing on well-known cellular pathways. Recently, however, researchers have discovered an unexpected player in this life-or-death drama: a gene called Flavin-containing monooxygenase 3 (FMO3).
Once considered a steady metabolic helper, FMO3 is now revealing itself as a dynamic master switch that can either exacerbate liver injury or help orchestrate its repair, depending on the context. This article explores the fascinating dual nature of FMO3 and how understanding its split personality might unlock new approaches to treating liver disease.
Flavin-containing monooxygenase 3 (FMO3) is an enzyme primarily produced in the liver that specializes in metabolizing foreign compounds. Think of it as one of the body's many chemical processing plants, transforming substances so they can be safely eliminated. For decades, FMO3 was considered a relatively stable enzyme whose main claim to fame was its role in a condition called trimethylaminuria (or "fish odor syndrome"), where its deficiency causes a distinctive body odor 1 .
Traditional scientific understanding held that FMO3 levels remained largely constant. However, groundbreaking research has revealed that FMO3 is anything but static. During various types of liver injury, FMO3 expression can change dramatically—sometimes increasing forty-fold or more 2 . This discovery transformed FMO3 from a background metabolic player to a potential key regulator in the liver's injury response system.
To understand how FMO3 behaves under stress, researchers designed a comprehensive study to examine its expression across different mouse models of liver injury 2 3 . This approach allowed them to determine whether FMO3 activation was specific to certain types of damage or a universal response.
Scientists divided mice into several groups, each subjected to a different type of liver injury:
The results revealed that not all liver injuries are equal in FMO3's eyes. The enzyme showed strikingly different responses depending on the type of insult:
| Injury Model | Effect on FMO3 mRNA | Effect on FMO3 Protein | Magnitude of Change |
|---|---|---|---|
| ANIT | Increased | Increased | 43-fold mRNA increase; 4-fold protein increase |
| Bile Duct Ligation | Increased | No change | 1899-fold mRNA increase |
| APAP | Increased | Increased | Significant increase |
| CCl4 | Decreased | Decreased | Significant decrease |
| Allyl Alcohol | No change | No change | No significant change |
This patchwork of responses indicated that FMO3 isn't simply a general stress responder but is selectively activated based on the specific nature of the injury. The astonishing 1899-fold increase in mRNA after bile duct ligation—one of the most dramatic gene inductions ever observed in liver injury—suggests FMO3 plays a particularly important role in cholestatic conditions.
Recent research reveals that FMO3 plays a complex, dual role in liver health—sometimes protective, sometimes damaging, depending on the context.
Emerging evidence shows that in certain types of drug-induced liver injury, FMO3 actively worsens the damage. A 2025 study discovered that elevated FMO3 interacts with a transcription factor called CREB3, suppressing its ability to activate protective genes. Simultaneously, FMO3 produces trimethylamine N-oxide (TMAO)—a molecule that triggers endoplasmic reticulum stress in liver cells through the PERK pathway 1 . This one-two punch both disables protective mechanisms and activates destructive ones, creating a vicious cycle of liver damage.
Paradoxically, in other contexts, FMO3 appears to be protective. During ageing, FMO3 upregulation mimics the beneficial effects of calorie restriction—a well-established intervention that delays ageing progression. In this scenario, increased FMO3 activates autophagy (cellular self-cleaning), reduces oxidative stress, improves lipid metabolism, and diminishes ageing markers in the liver 6 8 .
This Jekyll and Hyde character makes FMO3 both fascinating and challenging from a therapeutic perspective—the same enzyme that aggravates drug-induced injury might protect against age-related decline.
| Context | Role of FMO3 | Mechanism | Overall Effect |
|---|---|---|---|
| Drug-Induced Liver Injury | Aggravator | Inhibits CREB3/P4HB axis; increases TMAO-mediated ER stress | Worsens liver damage |
| Ageing Liver | Protector | Induces autophagy; reduces oxidative stress & inflammation | Retards liver ageing |
| Calorie Restriction | Mimetic | Mimics CR effects; enhances mTOR-regulated autophagy | Improves metabolic health |
Studying a complex enzyme like FMO3 requires specialized tools and approaches. Here are some key resources scientists use to unravel FMO3's mysteries:
Nrf2 knockout mice, Adipo-FMO3 KO mice, Bile duct ligation model
Test FMO3 regulation and function in different injury contexts and genetic backgroundsAPAP, ANIT, CCl4, Allyl Alcohol
Induce specific types of liver injury to observe FMO3 response3,3'-diindolylmethane (DIM), 3,3-dimethyl-1-butanol (DMB)
Block FMO3 activity or TMAO production to test therapeutic potentialDeuterated TMA (d9-TMA)
Trace TMAO production and metabolism in different tissuesAdeno-associated viruses (AAV8-Adv-FMO3), Western blotting, RNA sequencing
Manipulate and measure FMO3 expression and its downstream effectsThe discovery of FMO3's fluctuating behavior in liver injury has transformed our understanding of how the liver responds to damage. No longer just a metabolic housekeeper, FMO3 emerges as a dynamic regulator at the crossroads of injury, repair, and ageing.
The path from this discovery to new treatments remains challenging. The dual nature of FMO3 means that therapeutic approaches would need to be carefully targeted—potentially inhibiting FMO3 in cases of drug-induced liver injury while activating it to combat age-related decline. Researchers are already exploring compounds like 3,3-dimethyl-1-butanol (DMB) that can inhibit TMAO production and alleviate FMO3-mediated liver damage 1 .
As we continue to unravel the complexities of this fascinating enzyme, we move closer to a future where we can harness the liver's innate resilience more effectively, developing smarter treatments that work with the body's natural repair mechanisms rather than against them.
References will be added here in the final publication.