Narrative review: necroptosis–senescence crosstalk via mtDNA-cGAS-STING-PFKFB3 in kidney fibrosis
A narrative review proposes that necroptosis and senescence in tubular epithelial cells form a self-amplifying loop through a mitochondrial DNA–cGAS–STING–PFKFB3–glycolysis axis in tubulointerstitial fibrosis; the cited targeted strategies show preclinical efficacy only. [1]
Automatic summary · not editorially reviewed
The key findings
Renin-angiotensin system inhibitors and sodium-glucose cotransporter 2 inhibitors slow chronic kidney disease progression but cannot block or reverse tubulointerstitial fibrosis. [1]
The review proposes that mitochondrial DNA released by necroptotic tubular epithelial cells activates cGAS-STING-interferon regulatory factor 3-dependent PFKFB3 transcription, driving glycolysis that sustains the senescence-associated secretory phenotype. [1]
Inhibitors of receptor-interacting serine/threonine-protein kinase 1, senolytics, PFKFB3 blockers and multi-target traditional Chinese medicine show preclinical efficacy but face translation barriers. [1]
The source at a glance
- Study type / format
- Narrative review of peer-reviewed literature
- Population / context
- Tubular epithelial cells and interstitial fibroblasts in chronic kidney disease with tubulointerstitial fibrosis, as described in the reviewed literature.
- Summary based on
- Study abstract
- Original publication
- September 3, 2026
Review question on fibrosis progression
The review addresses chronic kidney disease, which progresses irreversibly toward tubulointerstitial fibrosis. Renin-angiotensin system inhibitors and sodium-glucose cotransporter 2 inhibitors slow progression but cannot block or reverse fibrosis. The authors state that necroptosis and cellular senescence in tubular epithelial cells are not independent events but form a dynamically evolving continuum.
Supporting source [1]
Proposed mtDNA-cGAS-STING-PFKFB3 loop
According to the review, necroptotic death of tubular epithelial cells releases mitochondrial DNA. This activates cyclic GMP-AMP synthase–stimulator of interferon genes–interferon regulatory factor 3-dependent transcription of PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3), driving glycolytic reprogramming. That reprogramming sustains and amplifies the senescence-associated secretory phenotype through lactylation of histone H4 lysine 12. Factors of this secretory phenotype activate interstitial fibroblasts and reciprocally prime neighbouring tubular epithelial cells for necroptosis, creating a self-amplifying loop.
Supporting source [1]
Preclinical strategies and translation barriers
The review lists inhibitors of receptor-interacting serine/threonine-protein kinase 1, senolytics, PFKFB3 blockers and multi-target traditional Chinese medicine. These show preclinical efficacy but face translation barriers from target selectivity, absence of biomarkers and ill-defined therapeutic windows. The authors suggest future antifibrotic strategies should shift from single-molecule inhibition to network remodeling, using chronology-based combination therapy tailored to disease stage and guided by dynamic biomarkers.
Supporting source [1]
How to interpret this
This explainer is based only on the abstract; the full text was not reviewed. The source is a narrative review, not a primary study, and reports no sample sizes, follow-up or effect estimates. The proposed axis and loop are described as a model, and the listed strategies are preclinical, not established human treatments.
Based on the study abstract; the full paper, tables and supplementary data were not reviewed.
Source & supporting passages
Wang D, Zheng H, Zhang X, Zhang C, Zhao D, Min S, Wang S. · europepmc.org · September 3, 2026