2026-06-17 | A toxic STING-SAMHD1 axis drives replication stress in progeria and cancer cells.
STING is an innate immune adaptor, classically activated by cytosolic DNA via cGAS-cGAMP to induce interferon signaling. Recent studies reveal that STING participates in non-canonical signaling pathways and localizes to the nucleus, where its functions remain poorly understood. In Hutchinson-Gilford Progeria Syndrome (HGPS), a premature aging disease caused by expression of the lamin-A mutant protein 'progerin', STING accumulates in the nucleus and drives chronic inflammation. Here, we show that replication stress is a trigger of STING nuclear accumulation and chromatin binding. In addition, we uncover that STING binds to nascent DNA and promotes replication stress in progeria and tumor cells. Mechanistically, STING causes replication fork slowing and stalling by limiting dNTPs availability. Upon fork stalling, STING hinders replication fork protection/stability by facilitating MRE11-mediated nascent DNA degradation (NDD). Importantly, STING's contribution to dNTP depletion and NDD is mediated by SAMHD1. Depletion of SAMHD1 phenocopies STING abrogation in reducing replication stress in progeria cells, and rescues replication fork speed and stability in STING-expressing tumor cells. These findings define a pathological STING-SAMHD1 axis that drives replication stress and genome instability in both progeria cells and tumor cells with elevated STING activity, uncovering a feedforward loop between innate immune signaling and impaired DNA replication.
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2026-05-22 | Discovery of NARF-interacting proteins.
Patients with Hutchinson-Gilford Progeria Syndrome manifest molecular defects in the nuclear lamina with unique phenotypic presentation in accelerated aging. The data in sum together with other biochemical and cellular studies suggested a central and critical role for the nuclear lamina in cellular aging, a process related to but separate from organismal aging. We used proteomics for unbiased discovery of NARF-interacting proteins.
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2026-05-10 | NLRP3 inflammasome dysregulation by endocrine-disrupting chemicals and heavy metals: Developmental programming, sex differences, and inflammaging across the lifespan.
Environmental exposure to heavy metals and endocrine-disrupting chemicals (EDCs) activates the NLRP3 inflammasome, driving chronic inflammation that worsens or may underlie cardiovascular disease, neurodegeneration, and accelerated aging. This review examines the molecular mechanisms by which lead, cadmium, mercury, arsenic, bisphenol A, phthalates, and dioxins modulate NLRP3 signaling. Lead and cadmium activate NLRP3 through mitochondrial dysfunction and oxidative stress, whereas mercury and arsenic suppress inflammasome assembly by preventing apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization. EDCs engage receptor-mediated pathways: aryl hydrocarbon receptor (AhR) activation directly represses NLRP3 transcription, yet bisphenol A and phthalates override this suppression through NF-κB activation. Developmental timing critically determines outcomes such as prenatal exposures epigenetically programing persistent NLRP3 dysregulation. Sex hormones have been shown to modulate distinct inflammatory landscapes: estrogen suppresses NLRP3 via ERβ-dependent mechanisms, while testosterone amplifies inflammasome-dependent pathology. The skin serves as a primary interface for environmental chemical exposure and cutaneous NLRP3 activation. NLRP3-deficient mice exhibit 34% increased lifespan, and pharmacological inhibition with MCC950 extends lifespan in progeria models. The CANTOS trial demonstrated that targeting inflammation through IL-1β neutralization confers cardiovascular benefits in high-risk humans. These findings position NLRP3 as a central integrator through which the chemical exposome accelerates inflammaging and identify inflammasome inhibition as a therapeutic strategy for environmental disease prevention.
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