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.

Recent Publications Focus

Below is a summary of the newest research publications targeting SIRT1/HIF-1α pathway (sorted by publication date).

Recent studies have continued to position the SIRT1/HIF-1α axis as a key regulator of metabolic, inflammatory, and hypoxia-related responses 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, leading to reduced expression of glycolytic enzymes, lower lactate and ATP production, and decreased oxidative stress; these effects were reversed by HIF-1α overexpression. In ischemic and hypoxic settings, HIF-1α also emerged as a relevant node in cerebral ischemia-reperfusion injury, obstructive sleep apnoea-associated mild cognitive impairment, and ischemic stroke, where it was linked to oxygen disturbance, cognitive impairment, angiogenesis, and inflammatory injury. A separate study of NADPH in ischemic stroke identified HIF-1α among the key predicted targets and found that treatment enhanced HIF-1α/VEGF-associated angiogenic responses while preserving blood-brain barrier integrity and suppressing NLRP3 inflammasome activation.

Several publications focused on SIRT1-centered interventions in inflammatory and neuroprotective contexts. Ginsenoside Rg3 improved cisplatin antitumor activity while mitigating nephrotoxicity through SIRT1-mediated suppression of the NLRP3 inflammasome, with the SIRT1 inhibitor Ex527 reversing the protective effects in renal cells. electroacupuncture after cerebral ischemia-reperfusion increased SIRT1 activity, inhibited NF-κB signaling, shifted astrocytes from the A1 to the A2 phenotype, and promoted synaptic recovery and functional improvement; the SIRT1 inhibitor Selisistat abolished these benefits. In neuropathic pain, CTRP3 alleviated mechanical allodynia and cold hyperalgesia by activating spinal SIRT1, thereby enhancing PGC-1α-mediated mitochondrial biogenesis and ATF5-driven mitochondrial unfolded protein response. Similarly, diosmetin reduced seizure severity and neuronal injury in epilepsy models while increasing SIRT1 expression, and SIRT1 inhibition reversed its anti-inflammatory and neuroprotective effects.

Other studies linked the pathway to oxidative stress, senescence, and tissue remodeling. resveratrol improved cognitive impairment in an Aβ1-42-induced Alzheimer’s disease model, reducing aging-related markers, attenuating reactive oxygen species production, and activating autophagy-associated signaling, with mechanistic involvement of the SIRT1/NF-κB pathway. In skin photoaging, SIRT1 activation by SRT1720 suppressed oxidative stress, DNA damage, cellular senescence, and extracellular matrix degradation through FOXO3a deacetylation and stabilization. In pulmonary fibrosis-related research, Ophiopogon japonicus and Qingluo Tongbi Formula were both reported to modulate HIF-1α-associated pathways in lung or hepatic injury contexts, while a mechanotherapeutic review highlighted SIRT1 as part of a broader mechanochemical framework linking tumor stress, ROS, and AMPK signaling. Collectively, these publications reinforce SIRT1/HIF-1α signaling as a convergent pathway in inflammation, hypoxia adaptation, metabolism, and tissue protection.

Result PMIDs

[PMID 41880677]
[PMID 42142137]
[PMID 42159899]
[PMID 42240069]

Target PMIDs

[PMID 41638470]
[PMID 41679357]
[PMID 41866771]
[PMID 41924840]
[PMID 42033852]
[PMID 42052680]
[PMID 42143107]
[PMID 42148594]
[PMID 42149357]
[PMID 42168722]
[PMID 42169649]
[PMID 42169654]
[PMID 42208379]
[PMID 42216775]
[PMID 42285238]
[PMID 42334617]
[PMID 42387373]
[PMID 42412302]