SIRT1/HIF-1α pathway

Overview

The SIRT1/HIF-1α pathway represents a critical regulatory axis bridging cellular energy sensing, oxygen homeostasis, and stress response. SIRT1 (sirtuin 1) is a NAD⁺-dependent deacetylase that governs a wide array of transcriptional programs by removing acetyl groups from both histone and non-histone substrates, thereby modulating inflammation, oxidative stress, mitochondrial biogenesis, and metabolic adaptation. HIF-1α (Hypoxia-Inducible Factor 1-alpha) is a master transcriptional regulator activated under hypoxic or pseudo-hypoxic conditions, orchestrating the expression of genes involved in angiogenesis, glycolysis, and cell survival. The two proteins intersect at multiple regulatory nodes: SIRT1 can directly deacetylate and suppress HIF-1α transcriptional activity, while HIF-1α activity may in turn affect NAD⁺ availability and SIRT1 function. This reciprocal relationship positions the SIRT1/HIF-1α pathway as a central hub in the cellular response to metabolic stress, inflammation, and hypoxia.

The pathway has broad pathophysiological relevance, influencing conditions ranging from ischemia-reperfusion injury, pulmonary fibrosis, neurodegeneration, and cancer to photoaging and metabolic dysfunction. Its capacity to integrate signals from the NLRP3 inflammasome, nuclear factor kappa B (NF-κB), Forkhead box O3 (FOXO3a), oxidative stress markers, and apoptotic pathways makes it an attractive pharmacological target across multiple disease domains.

Focus of Latest Publications

Recent publications have continued to examine the SIRT1/HIF-1α pathway as a mechanistic node linking metabolic stress, inflammation, and tissue injury across diverse disease models. In rheumatoid arthritis-associated interstitial lung disease, Glyasperin F was reported to upregulate Sirt1 and suppress PI3K/AKT/HIF-1α signaling, with downstream reductions in glycolytic enzymes, lactate/ATP production, and oxidative stress; HIF-1α overexpression reversed these effects. In a related pulmonary fibrosis context, Ophiopogon japonicus was studied for its effects on a HIF1A/TUBB3 axis associated with M2 macrophage polarization and arginine metabolic alterations. Another lung-focused study found that Qingluo Tongbi Formula attenuated Tripterygium wilfordii Hook. f.-induced hepatic metabolic dysfunction and oxidative stress via the SIRT1/HIF-1α pathway.

The pathway has also been implicated in ischemic and hypoxic injury. In cerebral ischemia-reperfusion injury, electroacupuncture was shown to activate SIRT1 while suppressing NF-κB phosphorylation, promoting astrocyte phenotypic switching from A1 to A2 and improving synaptic recovery; although HIF-1α was not the central focus of this study, it adds to the broader literature on SIRT1-linked stress responses in the injured brain. In acute ischemic stroke, a study on SLK highlighted USP8-mediated HIF-1α stabilization and RhoA/ROCK activation as part of the injury response. In ischemic stroke more broadly, NADPH was identified as acting through HIF-1α/VEGF signaling to preserve blood-brain barrier integrity, inhibit NLRP3 inflammasome-mediated damage, and stimulate angiogenesis. A pilot study in obstructive sleep apnoea with mild cognitive impairment also reported higher HIF-1α levels in affected patients and suggested a possible relationship with Tau phosphorylation via GSK-3β.

Additional publications linked SIRT1 and HIF-1α to cancer, toxicology, and systemic metabolic regulation. In lung cancer, ginsenoside Rg3 enhanced cisplatin antitumor activity and reduced nephrotoxicity through SIRT1-dependent suppression of the NLRP3 inflammasome. In gastric and colorectal cancer, a dual c-Met/COX-2 inhibitor was reported to block HIF-1α among other signaling pathways. In gestational diabetes research, PFAS exposure was associated with disrupted hepatic metabolic networks, and SIRT1 was identified as a critical regulatory hub alongside ESR1. Together, these studies portray the SIRT1/HIF-1α pathway as a recurring target in inflammation, hypoxia adaptation, metabolic dysfunction, and tissue remodeling, with therapeutic modulation explored through natural compounds, traditional formulas, electroacupuncture, and small-molecule interventions.

Key Publications

• NEWJul Targeting SLK protects against cerebral ischemia-reperfusion injury by regulating USP8-mediated HIF-1α stabilization and RhoA/ROCK activation. (Cellular & molecular biology letters, 2026, PMID 42387373): "Targeting SLK protects against cerebral ischemia-reperfusion injury by regulating USP8-mediated HIF-1α stabilization and RhoA/ROCK activation."
• NEWJun Mechanotherapeutic biomaterials: Overcoming physical barriers to enhance intratumoral drug delivery in solid tumours. (Biomedical microdevices, 2026, PMID 42334617): "The framework is further extended to incorporate mechanochemical coupling through the representative reactive oxygen species (ROS), AMP-activated protein kinase (AMPK), and sirtuin 1 (SIRT1), linking mechanical stress with redox and metabolic adaptation and informing responsive biomaterial design."
• NEWJun Ophiopogon japonicus alleviates pulmonary fibrosis through modulation of HIF1A/TUBB3 axis-associated M2 macrophage polarization and arginine metabolic alterations. (Journal of ethnopharmacology, 2026, PMID 42285238): "Although Ophiopogon japonicus has shown anti-inflammatory and anti-fibrotic potential in respiratory diseases, its pharmacological mechanisms against PF remain unclear."
• Jun Activation of Sirt1 by Glyasperin F Suppresses PI3K/Akt/HIF-1α Signaling and Inhibits Glycolytic Metabolism to Ameliorate Pathology in Rheumatoid Arthritis-Associated Interstitial Lung Disease. (FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2026, PMID 42216775): "Mechanistically, Glyasperin F upregulated Sirt1, thereby suppressing the PI3K/Akt/HIF-1α pathway, downregulating key glycolytic enzymes (HK2, PFK, PKM2, LDHA), and reducing lactate/ATP production and oxidative stress."
• May Per- and polyfluoroalkyl substances are associated with gestational diabetes and perturb hepatic metabolic regulatory networks: Convergent epidemiological, computational, and experimental evidence. (Ecotoxicology and environmental safety, 2026, PMID 42208379): "Estrogen receptor 1 (ESR1) and sirtuin 1 (SIRT1) were identified as critical regulatory hubs linking PFAS exposure to metabolic dysfunction."
• Jul Ginsenoside Rg3 potentiates cisplatin antitumor activity while mitigating nephrotoxicity through SIRT1‑mediated suppression of the NLRP3 inflammasome. (International journal of molecular medicine, 2026, PMID 42169649): "these effects were reversed by the SIRT1 inhibitor Ex527, implicating SIRT1 pathway dependency."
• May CTRP3 alleviates neuropathic pain by improving mitochondrial biogenesis and mitochondrial unfolded protein response via spinal SIRT1 in rats. (International journal of molecular medicine, 2026, PMID 42169654): "Mechanistically, pharmacological inhibition of SIRT1 with EX‑527, or siRNA‑mediated silencing of PGC‑1α or ATF5, reversed the effects of CTRP3 on pain hypersensitivity, mitochondrial biogenesis, UPRmt and oxidative stress."
• May Mild Cognitive Impairment Associated with Obstructive Sleep Apnoea: A Pilot Study on Oxygen-Related Plasma Biomarkers and Network Analysis. (Molecular neurobiology, 2026, PMID 42168722): "Notably, in the entire OSAS cohort, T90 positively correlated with HIF-1α levels, which were higher than controls, although not significantly."
• May Electroacupuncture Promotes Synaptic Recovery After Cerebral Ischemia-Reperfusion by Activating SIRT1 to Inhibit the NF-κB Pathway and Regulate Astrocyte Phenotypic Transformation. (Neurochemical research, 2026, PMID 42149357): "We hypothesized that EA drives this switch via the SIRT1-NF-κB axis to enhance synaptic recovery."
• May Betulinic acid is associated with miR-21 modulation, apoptosis and redox changes in breast cancer cells: an in vitro and in silico study. (Scientific reports, 2026, PMID 42143107): "Besides, the potential effect of BA and DOX treatment on downstream effect of miR-21 on HIF1A, PDCD4, PTEN and SMAD7 expression levels."