ArticleJournal of orthopaedic translation2026
USP39 inhibits MLKL phosphorylation and deubiquitination to suppress necroptosis of nucleus pulposus cells and attenuate intervertebral disc degeneration.
Article in Journal of orthopaedic translation, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
2 citing papers in PubMed.
- An SSK1-loaded decellularized annulus fibrosus matrix-based PD hydrogel alleviates intervertebral disc degeneration through modulation of NF-κB signaling and ferroptosis.Journal of orthopaedic translation · 2026Article
- Advancing the continuum of orthopaedic translation: Mechanistic insight, regenerative innovation, and converging technologies.Journal of orthopaedic translation · 2026Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
11 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Background: Intervertebral disc degeneration (IVDD) is a leading cause of chronic low back pain. Programmed cell death, particularly necroptosis, contributes to nucleus pulposus (NP) cell loss. Mixed lineage kinase domain-like protein (MLKL) phosphorylation plays a critical role in necroptotic execution, but its upstream regulation in IVDD remains poorly defined. Methods: We analyzed human and mouse degenerative disc tissues, as well as TNF-α/Smac mimetic/Z-VAD-FMK (TSZ)-treated NP cells, to assess MLKL phosphorylation. MLKL knockdown in human NP cells and conditional knockout (CKO) in mice were performed to determine its functional role. Immunoprecipitation coupled with mass spectrometry identified potential MLKL-binding proteins. Functional assays with USP39 knockdown/overexpression, together with in vitro and in vivo IVDD models, were conducted to explore regulatory mechanisms. Results: MLKL phosphorylation was markedly elevated in human IVDD tissues, LSI-induced mouse discs, and TSZ-stimulated NP cells. Genetic knockdown or conditional deletion of Mlkl significantly preserved extracellular matrix integrity and delayed degeneration. USP39 was identified as a novel MLKL-interacting deubiquitinase. USP39 expression was reduced in IVDD, and its overexpression inhibited MLKL ubiquitination and phosphorylation, alleviating NP cell degeneration. In vivo, AAV-mediated Usp39 delivery attenuated disc degeneration and suppressed MLKL activation. Conclusion: Our study reveals that MLKL phosphorylation drives necroptosis in IVDD and identifies USP39 as a critical upstream regulator that deubiquitinates MLKL. Targeting the USP39-MLKL axis provides a promising therapeutic strategy for delaying IVDD progression. The Translational Potential of this Article: This study reveals that USP39 inhibits MLKL phosphorylation through deubiquitination, thereby suppressing necroptosis of nucleus pulposus cells and alleviating IVDD. Targeting the USP39-MLKL axis provides a potential therapeutic strategy to preserve NP cell viability and slow the progression of IVDD, offering new insight for translational interventions in chronic low back pain.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.