For years, scientists have struggled to connect the diverse genetic and environmental factors associated with autism into a single coherent explanation.
Now, a researcher at the University of California (UC) San Diego School of Medicine has proposed a unified “three-hit” metabolic model. This new framework suggests that autism arises from a collision of genetic sensitivity, early life triggers and prolonged cellular stress.
The challenge of identifying unified autism causes
Autism has been studied for a century, yet pinning down a single cause has proven difficult. Researchers have identified hundreds of genetic risk factors, alongside environmental influences such as pollution, maternal infection and metabolic issues. While each area of study provides essential insights, it has been challenging to explain how such different factors can all lead to the same condition.
Hundreds of genes have been linked to autism, yet they don’t have the same effect in every child who carries them. Meanwhile, environmental factors increase risk during pregnancy and early life, when the brain is most sensitive to change. At the same time, many autistic children experience medical issues that involve metabolism or the immune system, which hints that autism affects the body more broadly than originally thought.
What’s been missing is a single model that can pull these threads together. Without that, findings about stress chemistry, immune activity, mitochondrial changes or shifts in the gut can feel scattered. Earlier work by author Dr. Robert Naviaux, a professor of medicine, pediatrics and pathology at UC San Diego School of Medicine, suggested that a built-in stress response, called the cell danger response (CDR), might help connect them. Studies across different conditions later found matching patterns in metabolism and immune signaling, adding weight to the idea.
Naviaux’s new paper introduces a “three-hit” model that links genes, early triggers and long-running stress signals.
A new three-hit metabolic model for autism
The review pulls together more than ten years of research across genetics, metabolism, toxicology and early brain development. The authors analyzed findings from many fields and used them to build a single model for how autism might arise.
To do this, Naviaux combined results from large genetic studies, multiomics research in autism and epidemiology work on environmental exposures. He also drew on mechanistic papers showing how stress, infection, toxic metals, air pollution or maternal illness influence mitochondria and chemical signaling inside cells.
Based on this evidence, he presented the “three-hit” model:
The first hit is genetic predisposition: some children inherit a “sensitive genotype” that makes their mitochondria and cellular signaling systems highly reactive to environmental changes. These can range from specific genetic syndromes to a combination of common variants. On their own, these genetic traits do not cause autism, but they create biological hypersensitivity to stress.The second hit occurs when the environment triggers this sensitivity. This happens during a critical window from early pregnancy through the first 18–36 months of life. Triggers can include maternal immune activation, pollution or metabolic stressors. In this model, early triggers push sensitive cells into a stress state at the wrong moment.The third hit is when that stress state continues for months during late pregnancy or early childhood. Long periods of cellular stress are proposed to disturb normal brain development, reshape mitochondria and influence gut microbes and the immune system.
Across these three hits, one mechanism ties the model together: a signaling molecule called extracellular ATP (eATP), a molecule that acts as a “danger signal”. When eATP levels stay high, cells remain in a defensive mode rather than returning to normal growth. Naviaux argues that this is not a malfunction, but rather mitochondria responding exactly as designed to a perceived threat.
“Behavior has a chemical basis. The CDR regulates that chemistry,” Naviaux explained. “When it remains activated too long, it diverts the body’s resources from normal growth and development toward cellular defense, leaving fewer resources for the developing brain.”
The review explains that the CDR is part of a universal healing cycle called salugenesis; in autism, this cycle gets stuck, preventing the return to normal cellular function. This prolonged stress prevents the necessary developmental shift from excitatory to inhibitory signaling in the brain, leading to over-excitation.
This framework also explains why many autistic children experience physical symptoms such as gut issues or sleep disturbances – signs of a body-wide stress response.
Naviaux points to phenylketonuria (PKU) as a proof-of-concept: PKU is a genetic disorder that causes severe disability if left alone, but with early metabolic treatment, children develop typically. He suggests a similar approach could one day be possible for autism.
Potential strategies for autism prevention and treatment
Instead of treating autism as mainly genetic, the review presents autism as a condition shaped by metabolism, immunity and early development.
One of the strongest claims in the paper is that up to half of autism cases might be reduced or prevented through support during pregnancy or early childhood. This estimate relies on the idea that the “second and third hits” are environmental and can be changed.
“Autism is not the inevitable result of any one gene or exposure, but the outcome of a series of biological interactions, many of which can be modified,” said Naviaux.
“By understanding how these genetic and environmental factors stack to alter a child’s developmental trajectory, we can start to imagine preventive care and new approaches to treatment that were previously thought impossible,” he added.
The model opens the door to new therapeutic ideas, including drugs that target ATP signaling, metabolic interventions that aim to settle the CDR and screening tools that look for early signs of metabolic stress in pregnancy or in newborns.
“If we can recognize and calm the cellular stress response before it becomes chronic, we may be able to improve or even prevent some of the most disabling symptoms,” said Naviaux.
However, the paper presents a theoretical model that requires further validation. Many of its claims rely on linking findings from different fields, which means some connections are suggestive rather than proven.
The idea that chronic CDR drives autism is debated, and measuring this activation in clinical settings remains a challenge. The estimate that early intervention could prevent a large share of cases is also speculative.
Taken together, the model is best viewed as a way to organize complex findings rather than a final answer to autism causation. It offers a framework that may help researchers bring together genetics, metabolism and environment in a more coordinated way.
“Understanding autism through the lens of metabolic signaling doesn’t just change how we think about the condition – it changes what we can do about it,” said Naviaux.
That idea will need careful testing, but it sets the stage for work that may probe autism risk and development from fresh angles.
Reference: Naviaux RK. A 3-hit metabolic signaling model for the core symptoms of autism spectrum disorder. Mitochondrion. 2026;87:102096. doi: 10.1016/j.mito.2025.102096
This article is a rework of a press release issued by the University of California – San Diego. Material has been edited for length and content.