Novel apoptosis signal-regulating kinase 1 (ASK1) inhibitor SRT-015: Potential therapeutic for multiple liver diseases

Human liver diseases, ranging from alcohol-associated liver disease (ALD) to metabolic-disease associated steatohepatitis (MASH), often converge on a shared destructive endgame: inflammation, cell death (apoptosis), and scarring (fibrosis). While the initial causes differ—whether it is toxin ingestion, infection, or metabolic stress—the biological machinery driving the progression toward cirrhosis is remarkably similar.

A central player in this process is ASK1 (apoptosis signal-regulating kinase 1), a redox-sensitive protein that acts as a cellular "emergency switch." When the liver is under oxidative stress, ASK1 activates. This triggers downstream signaling cascades that tell cells to inflame, die, or trigger the fibrotic response. Scientists have long targeted ASK1 to halt these pathways, but previous attempts have hit a wall. Earlier inhibitors, such as selonsertib, failed in clinical trials for MASH and ALD. This failure was likely due to off-target liabilities—side effects where the drug interferes with unintended biological processes.

A new study from Seal Rock Therapeutics introduces SRT-015, a novel small-molecule inhibitor designed to bypass these historical failures. The researchers report that SRT-015 effectively shuts down the ASK1 pathway across multiple diverse liver disease models without the safety concerns that sidelined its predecessors.

The failure of early ASK1 inhibitors

The pursuit of ASK1 inhibition has been hampered by a fundamental trade-off between potency and selectivity. To stop liver damage, a drug must inhibit the ASK1 kinase—the engine driving the stress response—without causing collateral damage to other vital systems.

Previous candidates like selonsertib encountered significant hurdles. The authors note that selonsertib demonstrated off-target liabilities. These included risks of cardiac QT prolongation (a disturbance in the heart's electrical rhythm) and unintended cytotoxicity (cell toxicity) in non-stressed cells. Furthermore, in a therapeutic model of MASH, selonsertib was found to be ineffective at reducing liver inflammation and fibrosis. This occurred even when the drug reached plasma levels similar to those used in clinical trials. This suggests that simply hitting the target isn't enough. The drug must do so with high precision and a clean safety profile to be clinically viable.

Precision targeting of the ASK1 switch

The researchers engineered SRT-015 to occupy the ATP-binding pocket of the ASK1 kinase. By doing so, the molecule prevents the protein from auto-phosphorylating. This is a process where the protein adds a phosphate group to itself to "turn on." Blocking this step stops the downstream signaling of JNK and p38 MAP kinases.

The mechanism of action follows a multi-pronged approach across different cell types: 1. In immune cells (PBMCs), SRT-015 inhibits the release of pro-inflammatory cytokines like TNF. 2. In hepatocytes (liver cells), it prevents ROS-induced apoptosis. This essentially stops the "suicide" signal triggered by oxidative stress. 3. In fibroblasts (cells that produce connective tissue), it inhibits the transition into myofibroblasts, which are the drivers of excessive scarring.

The authors demonstrate this selectivity through kinome scanning. They tested the compound against 489 different kinases. As shown in [Figure 1B], SRT-015 displays a highly selective profile. Only a handful of kinases showed significant inhibition, primarily focusing on the intended ASK1 target [Figure 1C].

Evidence across acute and chronic models

The strength of the study lies in its breadth. It tests SRT-015 in environments ranging from sudden chemical injury to long-term metabolic disease. In acute models of acetaminophen (APAP) overdose and alcohol-associated liver disease (ALD), the authors report that SRT-015 dose-dependently decreased serum ALT (a standard biomarker for liver injury) [Figure 3A, 3C].

The most striking evidence comes from a chronic, diet-induced obesity (DIO)-MASH model. Researchers used a therapeutic diet to administer SRT-015 at concentrations of 0.3% or 0.5%. Unlike selonsertib, which failed to impact liver health in this model, SRT-015 treatment significantly inhibited hepatomegaly (liver enlargement), liver enzymes, fibrosis, inflammation, and apoptosis [Figure 4D-G]. Crucially, the authors report these benefits occurred independently of any changes in body weight. This suggests the drug acts directly on the liver pathology rather than through systemic metabolic shifts.

The antifibrotic efficacy was further validated in a rat model of cholestatic disease (bile duct obstruction). The study finds that SRT-015 significantly decreased fibrosis and prevented the activation of stellate cells. These cells are the primary architects of liver scarring .

Assessing the gaps in the data

While the preclinical results are robust, several questions remain for future development. First, the study relies heavily on rodent and non-human primate models. While these are standard, translating "pleiotropic" (multi-effect) efficacy from mice to humans is rarely a straight line.

Second, the authors note that certain high-resolution analyses, specifically RNAseq, were not performed for the 0.3% SRT-015 DIO-MASH group. Finally, although the study demonstrates a lack of hERG inhibition, long-term safety profiles in much larger biological systems have yet to be established. The current data provides a "mechanistic proof of concept." However, it does not yet account for the complex drug-drug interactions a patient might experience in a real-world clinical setting.

The verdict: A promising pivot for liver therapy

If the preclinical trajectory holds, SRT-015 represents a significant technical improvement over the first generation of ASK1 inhibitors. By solving the dual problems of off-target toxicity and poor functional efficacy in chronic models, the authors have moved the needle from "target validation" to "candidate optimization."

The drug's liver-selective pharmacokinetics is a major advantage. It concentrates in the liver and kidneys while maintaining low systemic levels .

This helps minimize side effects. Given its ability to address inflammation, fibrosis, and apoptosis simultaneously, SRT-015 is a strong candidate for combination therapy. It could potentially work alongside metabolic treatments like GLP-1 agonists. It is not ready for the clinic today, but it is a highly credible contender for upcoming human trials.

Figures from the paper