Blocking Src kinase reduces neuroinflammation by activating microglial mitophagy in mice
Inhibiting the kinase reduced p62 UFMylation to promote ubiquitination and mitochondrial clearance, alleviating cognitive deficits in mice.
Biochemical pharmacology · Dong YR et al. · Paper published 25 Sep 2026
In mice and cell models exposed to lipopolysaccharide, pharmacological inhibition of Src tyrosine kinase reduced neuroinflammatory responses. Proteomic analysis revealed that Src regulates microglial mitophagy through a pathway involving p62 UFMylation. Blocking Src kinase decreased the phosphorylation of the E3 ligase UFL1, which reduced the UFMylation of p62. Because UFMylation and ubiquitination compete for the same residue on p62, lower UFMylation facilitated p62 ubiquitination and subsequent degradation. This process induced microglial mitophagy and alleviated neuroinflammation. In the lipopolysaccharide-treated mice, Src inhibition ameliorated neuroinflammatory pathology and improved cognitive deficits via this p62-dependent mitophagy mechanism.
Why it matters
Chronic neuroinflammation and defective mitochondrial clearance are central drivers of neurodegenerative conditions such as Alzheimer's disease. Identifying the Src-UFL1-p62 axis highlights a potential molecular strategy to restore microglial mitophagy and preserve neuroimmune homeostasis.
Caveats
The findings rely on mice and cell cultures subjected to acute lipopolysaccharide exposure rather than aged models or clinical neurodegeneration. Whether targeting Src produces safe and comparable neuroprotective outcomes in humans remains unknown.
Written from the paper’s abstract, and every claim checked against it before publishing. Read the paper for the full methods and data.
The paper
Src inhibition attenuates neuroinflammation via promoting p62 UFMylation-dependent microglial mitophagy
Dong YR, Wang JR, Yang Y et al.
Biochemical pharmacology · 25 Sep 2026 · Peer-reviewed
- Relevance
- Relevant
- News value
- Notable
- Evidence
- Animals
- Status
- Peer-reviewed
More on Mitochondria
See allCardiolipin loss drives muscle fiber shifts during aging via a nuclear receptor
Restoring cardiolipin synthesis in knockout mice reversed muscle atrophy and prevented premature death.
Nature aging · Finger F et al.
Early-life mitochondrial DNA mutations drive age-related pathology in mice
Manipulating mitochondrial fusion can alter tissue-specific selection against deleterious variants that arise early in development.
bioRxiv · Shemtov SJ et al.
Inhibiting miR-128-3p restores muscle mass and function in aged mice
The microRNA inhibitor also improved cardiac outcomes after infarction and reduced pathology in mouse and pig models of muscular dystrophy.
bioRxiv : the preprint server for biology · Boldridge MA et al.
Prodh2 inhibition alleviates muscle atrophy and restores strength in COPD mice
TNF-alpha triggers a mitochondrial immune pathway via Prodh2 that damages myoblasts, while silencing the enzyme restores muscle strength in mice.
Aging cell · Chen G et al.
Depp1 drives muscle loss under fasting and low oxygen in mice
The study reveals that the protein localizes to mitochondria to regulate autophagy and mitochondrial degradation during nutrient and oxygen limitation.
bioRxiv · Qayyum S et al.