HSP90AA1

Overview

HSP90AA1 (Heat Shock Protein 90 Alpha Family Class A Member 1; Wikidata: Q18027367) is a human gene encoding the cytosolic, stress-inducible isoform of the 90 kDa heat shock protein (HSP90α), a highly conserved ATP-dependent molecular chaperone. As a member of the HSP90 family, HSP90AA1 plays a central role in the folding, stabilization, maturation, and degradation of a broad repertoire of client proteins — including kinases, transcription factors, and steroid hormone receptors — thereby functioning as a master regulator of cellular proteostasis. Its expression is markedly upregulated under conditions of cellular stress, including elevated temperature, hypoxia, and oxidative stress, which has positioned it as a sentinel of the cellular stress response. HSP90AA1 is also a critical scaffold within signal transduction networks, mediating the activity of oncoproteins and pro-survival pathways such as PI3K/Akt/mTOR and STAT3/HIF-1α, among others.

The broad involvement of HSP90AA1 in oncogenic signaling, inflammation, and metabolic disease has made it a high-priority therapeutic target across numerous disease contexts. Its overexpression in malignant tissues relative to normal counterparts enables tumor-selective targeting strategies. Beyond oncology, accumulating evidence implicates HSP90AA1 in cardiovascular diseases, neurodegeneration, fibrosis, and diabetic complications — underscoring the gene's pleiotropic biological significance and therapeutic versatility.

Focus of Latest Publications

Recent publications have repeatedly positioned HSP90AA1 as a hub target in network pharmacology, multi-omics, and molecular docking studies across cancer, toxicology, and neurobiology. In cancer-focused work, HSP90AA1 was identified among key hub nodes in a polyherbal nutraceutical formula (Vernolac) studied for anticancer potential, alongside targets such as Akt1, BCL2, EGFR, ESR1, SRC, STAT3, and TNF. Similar target-centric analyses also highlighted HSP90AA1 in lung adenocarcinoma in the context of per- and polyfluoroalkyl substance exposure, in hepatocellular carcinoma alongside RFC4, TOP2A, AURKA, and MCM4, and in oral squamous cell carcinoma where HSP90AA1 and HSP90AB1 were upregulated and associated with poorer survival. These studies used target prediction, protein-protein interaction mapping, enrichment analysis, and docking to connect HSP90AA1 with cancer-related pathways and therapeutic response.

Several reports specifically examined HSP90AA1 as a mechanistic mediator of bioactive compounds or nutritional interventions. In oral squamous cell carcinoma, hippeastrine was shown to bind HSP90 and Akt1, suppress the HSP90-PI3K-Akt-mTOR axis, and inhibit cell viability, colony formation, migration, and invasion in CAL27 and SCC-9 cells; rescue with the PI3K activator 740 Y-P reversed these effects. In hepatocellular carcinoma, quercetin was predicted to bind HSP90AA1 and other hub proteins, and it downregulated HSP90AA1 expression in HepG2 cells while inhibiting cell viability. In diabetic nephropathy, docosahexaenoic acid-acylated astaxanthin ester was linked to a colon-kidney axis involving trehalose and HSP90AA1; trehalose was identified as a putative HSP90AA1 target, and HSP90AA1 knockdown enhanced trehalose’s suppression of profibrotic gene expression in TGF-β1-challenged glomerular mesangial cells.

Outside oncology and renal disease, HSP90AA1 was implicated in neuronal injury, oxidative stress, and fibrosis-related signaling. A study of sevoflurane in elderly postoperative cognitive dysfunction identified HSP90AA1 as a key hub target and reported that sevoflurane increased HSP90AA1 expression, oxidative stress, mitophagy markers, and apoptosis in HT22 hippocampal neurons; knockdown of HSP90AA1 reversed these injury effects. In Yinxingye tablets, HSP90AA1 was among the hub targets associated with antioxidant stress effects, together with SRC, CASP3, MAPK8, MMP9, IGF1, RAF1, and PPARG. Another study on pulmonary fibrosis proposed that diammonium glycyrrhizinate and vitamin D3 act through crosstalk involving STAT3/HSP90AA1 and the HIF-1α pathway, indicating a role for HSP90AA1 in epithelial-mesenchymal transition-related signaling.

Collectively, these publications portray HSP90AA1 as a broadly connected stress-response and signaling hub that is repeatedly prioritized by computational target discovery and then supported by experimental validation. Across the studies, HSP90AA1 was linked to apoptosis, mitophagy, oxidative stress, inflammation, PI3K/Akt/mTOR signaling, and fibrosis-related pathways, and it emerged as a potential mediator of responses to compounds such as quercetin, hippeastrine, trehalose, and sevoflurane. The recurring use of docking, molecular dynamics, enrichment analysis, and cell-based rescue experiments suggests that HSP90AA1 remains an important target for understanding disease mechanisms and for evaluating multi-component therapeutics.

Key Publications

• NEWJul A network pharmacology-based approach and molecular docking study to explore the therapeutic potential of a nutraceutical formula (Vernolac) in the treatment of cancer. (PloS one, 2026, PMID 42384725): "Protein-protein interaction analysis using STRING and Cytoscape revealed fourteen key hub nodes, including AKT1, BCL2, CASP3, CTNNB1, EGFR, ESR1, GAPDH, HSP90AA1, HSP90AB1, IL6, JUN, SRC, STAT3, and TNF."
• NEWJun Exploring Sevoflurane promotes hippocampal neuron mitophagy in elderly postoperative cognitive dysfunction by HSP90AA1 based on network pharmacology. (Experimental brain research, 2026, PMID 42370964): "This study aims to investigate whether Sevoflurane regulates mitophagy in hippocampal neurons in elderly POCD through HSP90AA1, using a network pharmacology-based approach."
• NEWJun Multi-omics investigation of per- and polyfluoroalkyl substances in lung adenocarcinoma: comprehensive network toxicology, machine learning and molecular docking experiments. (Molecular diversity, 2026, PMID 42334505): "Consequently, we identified six hub toxicological targets: HSP90AA1, EGFR, AKT1, ALB, SRC, and ESR1, highlighting their potential central roles in PFAS-driven LUAD pathogenesis."
• Jun Integrative Database-Driven In Silico and In Vitro Study of Anemarrhena asphodeloides Bunge Highlighting Hippeastrine as a Regulator of the HSP90/PI3K/Akt/mTOR Axis in Oral Squamous Cell Carcinoma. (Advanced biology, 2026, PMID 42216572): "...with HSP90AA1, HSP90AB1, and CASP3 upregulated in OSCC, linked to poorer survival."
• Jun Integrative bioinformatics and experimental validation reveal quercetin as a potential multi-target therapeutic agent in hepatocellular carcinoma. (Cytotechnology, 2026, PMID 42145839): "Among these, the five most significant hub genes-RFC4, TOP2A, AURKA, HSP90AA1, and MCM4-were selected for further analysis."
• May Ameliorative effect of docosahexaenoic acid-acylated astaxanthin ester on diabetic nephropathy: association with the trehalose/HSP90AA1 and colon-kidney axis. (Food & function, 2026, PMID 42149022): "Combined network pharmacology and molecular docking assays identified HSP90AA1 as a putative molecular target of trehalose."
• Jun Integrated UPLC-QTOF-MS and Network Pharmacology for Predicting Active Constituents and Pharmacological Mechanisms of Yinxingye Tablets Against Oxidative Stress. (Biomedical chromatography : BMC, 2026, PMID 42104588): "Based on virtual target prediction, 211 targets of 76 active constituents with identifiable structures were identified, and HSP90AA1, SRC, CASP3, MAPK8, MMP9, IGF1, RAF1, and PPARG were defined as the hub targets involved in the antioxidant stress effects of Yinxingye tablets."
• Apr Robust transcriptomic hallmarks targeting intratumor heterogeneity in intrahepatic cholangiocarcinoma. (Cell reports. Medicine, 2026, PMID 41916296): "Therapeutically, HSP90 inhibition synergizes with anti-PD1 in inflammatory iCCA, whereas combined anti-PD1 and anti-TIM3 suppresses neurodegenerative iCCA."
• Apr Human iPSC-derived exosomes for amelioration of Huntington's disease through mitochondrial, synaptic, and anti-apoptotic mechanisms. (Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 2026, PMID 41846052): "iPSC-exo were isolated from iPSC-conditioned medium and characterized by nanoparticle tracking analysis, Western blotting, and ExoView assays, confirming exosomal size (∼100 nm) and expression of canonical markers (CD63, CD81, ALIX, HSP70/90)."
• May The HSP90-dependent bioorthogonal PROTAC prodrug system enables tumor-selective and enhanced protein degradation. (Journal of controlled release : official journal of the Controlled Release Society, 2026, PMID 41839264): "We developed a heat shock protein 90 (HSP90)-dependent bioorthogonal PROTAC prodrug system (HBPROTAC) to achieve tumor-specific target proteolysis."