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. 2025 Dec 6;34(1):495–507. doi: 10.1007/s10787-025-02072-7

Neuroprotective effects of SRS11-92 against oxidative stress–induced senescence via Nrf2/HO-1/NF-κB in Alzheimer’s disease models

Yu Guo 1,2, Huan Cao 1, Chengchao Zuo 3, Yaqi Huang 1, Zhongya Gu 1, Yu Song 1, Xiang Chen 1, Qingqing Jiang 4,✉, Furong Wang 1,2,4,✉
PMCID: PMC12855239  PMID: 41350486

Abstract

Background

Oxidative stress, neuroinflammation, and cellular senescence interact to drive Alzheimer’s disease (AD) progression. SRS11-92 is a redox-active small molecule with reported cytoprotective effects. This study sought to determine whether SRS11-92 mitigates Aβ-evoked oxidative stress and cellular senescence, and to delineate the underlying mechanism.

Methods

SH-SY5Y cells were challenged with Aβ25-35 and pretreated with SRS11-92. Oxidative stress (ROS, MDA, SOD activity, and GSH), inflammatory mediators (TNF-α, IL-1β, and IL-6), senescence markers (SA-β-gal, p53, p16, and p21), and Nrf2/HO-1/NF-κB proteins were quantified. Pathway dependence was assessed using the selective Nrf2 inhibitor ML385. 3xTg-AD mice received SRS11-92 for 6 weeks; cognitive function was assessed by novel object recognition, cortical neuronal integrity was assessed by Nissl staining, and cellular senescence in the hippocampus was evaluated by SA-β-gal.

Results

SRS11-92 attenuated Aβ25-35-induced cytotoxicity in a dose-dependent manner in SH-SY5Y cells, reduced ROS and MDA, and restored SOD activity and GSH. It suppressed TNF-α, IL-1β, and IL-6, decreased the percentage of SA-β-gal-positive cells, and downregulated p53, p16, and p21. Mechanistically, SRS11-92 increased total and nuclear Nrf2 and upregulated HO-1, while restricting NF-κB p65 nuclear translocation. ML385 abrogated these molecular and phenotypic benefits, confirming that SRS11-92 acts via the Nrf2 pathway in vitro. In 3xTg-AD mice, SRS11-92 improved cognitive function, partially rescued cortical Nissl-positive neurons, and reduced the hippocampal SA-β-gal-positive burden.

Conclusions

SRS11-92 exerts significant neuroprotective effects, attributable to reducing stress-induced senescence via activating Nrf2/HO-1 and constraining NF-κB signalling.

Keywords: Alzheimer’s disease, SRS11-92, Cellular senescence, Oxidative stress, Nrf2/HO-1, NF-κB p65 nuclear translocation

Introduction

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterised by memory loss and cognitive decline, imposing substantial healthcare and socioeconomic burdens worldwide (Scheltens et al. 2021). Medical treatment of AD mainly comprises acetylcholinesterase (AChE) inhibitors, N-methyl-D-aspartate (NMDA) receptor antagonists, and monoclonal antibodies (Lecanemab and Aducanumab). Reported adverse effects include headache, visual abnormalities, delirium, increased confusion, disorientation, gastrointestinal complaints, seizures, tiredness, and muscle cramps (Alzheimer’s Association 2023; Faldu and Shah 2024). The approved treatments for AD are not only expensive and few in variety, but also provide limited or predominantly symptomatic relief (Faldu and Shah 2024). Brain ageing is closely related to the occurrence of age-related neurodegenerative diseases, such as AD and Parkinson’s disease. Early identification and timely intervention of brain ageing are an important strategy for the prevention and treatment of AD (Liu et al. 2025). Therefore, developing novel anti-ageing drugs is of considerable prospective value.

Among its hallmark pathologies, aggregation of amyloid-β (Aβ) is closely linked to redox imbalance and neuroinflammation (Garcia-Agudo et al. 2024; Shin et al. 2019). Excessive reactive oxygen species (ROS) damages lipids, proteins, and DNA, fostering mitochondrial dysfunction (Zhang et al. 2021a; Cheignon et al. 2018) and propagation of the senescence-associated secretory phenotype (SASP) that amplifies tissue inflammation and neuronal dysfunction (Melo Dos Santos et al. 2024; Terao et al. 2022). Experimental evidence further indicates that Aβ oligomers induce senescence-like changes in neural cells such as oligodendrocyte progenitor cells (Zhang et al. 2019) and adult hippocampal neural stem/progenitor cells (He et al. 2013), and pharmacological clearance of senescent cells mitigates pathology and improves cognition in AD models (Cheignon et al. 2018). These studies support targeting oxidative stress and neuronal senescence concurrently to slow AD progression.

Nuclear factor erythroid 2–related factor 2 (Nrf2) is a master transcription factor that regulates the expression of a wide range of antioxidant and cytoprotective genes (Qu et al. 2020; Zhang et al. 2021b; Zgorzynska et al. 2021). Disruption of antioxidant defences is a key driver of cellular senescence (Kubben et al. 2016). Nrf2 dysfunction contributes to AD pathogenesis, including the accumulation of Aβ (Kanninen et al. 2008) and hyperphosphorylated Tau (Guan et al. 2022). Upon activation, Nrf2 translocates into the nucleus and drives downstream pathways to form the Nrf2/ antioxidant response element (ARE) signalling pathway. Among Nrf2-regulated genes, haem oxygenase-1 (HO-1) is a classical downstream effector with potent antioxidant properties (Chen-Roetling and Regan 2017; O’Rourke et al. 2024). Crosstalk between the Nrf2/HO-1 axis and nuclear factor-κB (NF-κB) critically shapes cellular responses to oxidative stress and senescence (Ganesh Yerra et al. 2013; Wu et al. 2023). The activity of Nrf2 declines with ageing and is dysregulated in AD (Osama et al. 2020; Silva-Palacios et al. 2018), making cells more susceptible to oxidative stress and promoting senescence (Kubben et al. 2016; Qiu and Liu 2022; Jiang et al. 2023). Taken together, targeting the Nrf2/HO-1 and NF-κB signalling pathways may offer a promising therapeutic strategy for AD.

SRS11-92 is a promising candidate compound based on preclinical studies (Skouta et al. 2014; Chen et al. 2023; Cotticelli et al. 2019) that exhibits a wide range of pharmacological properties, regulating oxidative stress, inflammation, and neuronal regeneration via multiple signalling pathways (Chen et al. 2023; Takeguchi et al. 2024). It reduces frataxin deficiency–induced cell death in human fibroblasts (Cotticelli et al. 2019). Skouta and colleagues demonstrated that it inhibits erastin-induced ferroptosis in HT-1080 human fibrosarcoma cells (Skouta et al. 2014), and that it effectively protects both human and mouse cellular models of Friedreich’s ataxia characterised by heightened oxidative stress and ferroptosis (Cotticelli et al. 2019). It has been shown that SRS11-92 preserves neuronal morphology, alleviates cognitive impairment, activates Nrf2 signalling, and attenuates neuronal ferroptosis in mice with ischaemia/reperfusion injury (Chen et al. 2023). However, whether SRS11-92 counteracts Aβ-induced oxidative stress and cellular senescence in AD-related models, and whether these effects require Nrf2 signalling, has not been established.

This study investigated the effects of SRS11-92 in Aβ25-35–challenged SH-SY5Y cells and in 3xTg-AD mice. Oxidative stress, inflammatory mediators, and cellular senescence were evaluated, and mechanistic interrogation focused on the Nrf2/HO-1/NF-κB axis, including pharmacological blockade using the selective Nrf2 inhibitor ML385. We hypothesised that SRS11-92 activates Nrf2/HO-1 and constrains NF-κB to mitigate Aβ-induced oxidative stress and senescence, and that these actions translate into cognitive and histological benefits in vivo.

Materials and methods

Chemicals and reagents

MEM/F12 was purchased from Procell (Wuhan, China). Fetal bovine serum (FBS) and penicillin/streptomycin were obtained from Boster Biological Technology (Wuhan, China). The treatment reagent Aβ25-35 was obtained from MedChem Express (New Jersey, USA). SRS11-92 and ML385 were obtained from Selleck (Houston, USA). The chemical structure of SRS11-92 is shown in Fig. 1. The senescence-associated β-galactosidase (SA-β-gal) staining kit and ROS assay kit were obtained from Beyotime (Shanghai, China). DMSO was purchased from Sigma-Aldrich (St. Louis, MO, USA). The MTT assay kit was obtained from Servicebio (Wuhan, China). ELISA kits for MDA and SOD were purchased from Solarbio (Beijing, China). ELISA kits for GSH, TNF-α, IL-1β, and IL-6 were purchased from Elabscience (Wuhan, China). NE-PER Nuclear and Cytoplasmic Extraction Kit was obtained from Thermo Fisher Scientific (Waltham, MA, U.S.A.). Antibodies for p53, p16, HO-1, GAPDH and β-actin were purchased from Proteintech (Chicago, IL, USA). The antibody for p21 was obtained from Abcam (Cambridge, UK). Antibodies for Nrf2, Histone H3 and NF-κB p65 were purchased from CST (Massachusetts, USA.).

Fig. 1.

Fig. 1

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Chemical structure of SRS11-92

Cell culture and treatment

STR-authenticated SH-SY5Y cells were purchased from Procell (Wuhan, China) and cultured in MEM/F12 containing 15% FBS and 1% penicillin–streptomycin under 5% CO2 at 37 °C. As described previously (Huang et al. 2024), Aβ25-35 was diluted to 1 mM with sterilised deionised water and then incubated for 1 week at 37 °C to induce aggregation. For experiments, it was diluted in culture medium to the indicated concentrations; vehicle (deionised water) served as control. Cells were incubated with SRS11-92 and/or ML385 at the indicated concentrations.

Cell viability analysis

SH-SY5Y cells were seeded into 96-well plates at a density of 5 × 103 cells/well and incubated for 24 h. Cell viability was assessed using the MTT assay according to the manufacturer’s instructions. To evaluate Aβ25-35 cytotoxicity, cells were treated with 0, 2.5, 5, 10, 20, and 40 μM for 48 h. To determine SRS11-92 toxicity, cells were treated with 0, 0.25, 0.5, 1, 2, 4 μM for 48 h. To assess the protective effect of SRS11-92 against Aβ25-35-induced cytotoxicity, cells were pretreated with SRS11-92 (0, 0.25, 0.5, 1, 2, 4 μM) for 4 h, followed by exposure to 20 μM Aβ25-35 for an additional 48 h. After treatment, the medium was removed, and cells were incubated with 10 μL of MTT working solution at 37 °C for 4 h. Formazan crystals were dissolved in DMSO, and absorbance was measured at 570 nm using a microplate reader. Cell viability was expressed as a percentage relative to the vehicle control.

Morphological observations

SH-SY5Y cells in the logarithmic growth phase were seeded at 1 × 105 cells/mL in 6-well plates and allowed to adhere for 24 h. Cells were then treated with SRS11-92 (0, 0.25, 0.5, 1, 2, or 4 μM) for 4 h, followed by exposure to 20 μM Aβ25-35 or vehicle for an additional 48 h. Cell morphology was assessed, and images were acquired on a phase-contrast microscope (Olympus, Tokyo, Japan).

ROS generation analysis

ROS levels were measured by dichlorodihydrofluorescein diacetate (DCFH-DA) using a ROS Detection kit (Beyotime, Shanghai, China) as previously described (Xie et al. 2023). After treatments, cells were incubated with 10 μM DCFH-DA solution at 37 °C for 30 min, rinsed with PBS to remove non-specific staining, and imaged under a fluorescence microscope (Olympus, Tokyo, Japan).

Intracellular superoxide dismutase (SOD), reduced glutathione (GSH), and Malondialdehyde (MDA) determination

MDA, SOD, and GSH levels were determined using the respective assay kits according to manufacturers’ protocols. A bicinchoninic acid (BCA) protein assay kit (Beyotime, Shanghai, China) was used to measure the protein content. Absorbance was measured with a microplate reader as above.

Inflammatory cytokines assay

Culture supernatants were collected after 48 h and clarified by centrifugation. TNF-α, IL-1β, and IL-6 were measured by ELISA according to the manufacturer’s instructions.

Total and nuclear protein extraction

Samples were washed with ice-cold PBS. For whole-cell lysates, cells were extracted in RIPA buffer with protease and phosphatase inhibitors. For subcellular fractionation, nuclear and cytoplasmic extracts were prepared using the NE-PER nuclear and cytoplasmic extraction kit (Thermo Fisher Scientific, Waltham, MA, USA) according to the manufacturer’s instructions. Lysates were cleared by centrifugation (12,000 g, 10 min, 4 °C). Protein concentration was determined by the BCA assay prior to adding sample buffer. Equal amounts of protein were mixed with loading buffer, heated at 95 °C for 5 min, and used immediately or snap-frozen at − 80 °C.

Western blotting

A total of 20 μg protein was separated by 8–12% SDS-PAGE, transferred to PVDF membranes, and blocked with 5% skimmed milk for 1 h at 37 °C. Membranes were incubated with primary antibodies overnight at 4 °C. After washing with TBST, membranes were incubated with HRP-conjugated secondary antibodies for 1 h. Signals were detected using a Bio-Rad ChemiDoc XRS + system with a high-sensitivity ECL kit, and quantitative analysis was carried out using ImageJ software.

Animal treatment

Homozygous 3xTg-AD mice (APPswe /PS1m146v/TauP301L) were obtained from Jackson Laboratories, with age-matched wild-type controls (hybrid progeny of C57BL/6 J × 129S1/SvImJ) (Hamilton et al. 2022). Procedures complied with institutional and national guidelines and were approved by the relevant ethics committees. Mice were group-housed at 23 ± 2 °C, 60–70% humidity, 12-h light/dark cycle, with ad libitum food and water. In this study, mice were 12 months old at baseline. Animals were randomly assigned to WT + Vehicle, WT + SRS11-92, AD + Vehicle, and AD + SRS11-92. SRS11-92 was dissolved in 5% DMSO and 95% corn oil and administered intraperitoneally at 2 mg/kg. Vehicle groups received equal volumes of solvent. After behavioural testing, mice under deep anaesthesia were killed by transcardial perfusion with pre-cooled 0.9% physiological saline. Brains were removed and stored at − 80 °C. Serial coronal frozen sections (20 μM) were cut using a cryostat (CM1950, Leica Biosystems, Wetzlar, Germany) and stored at − 80 °C.

Novel object recognition (NOR) testing

The NOR test was conducted according to established protocols with minor modifications (Cantarella et al. 2015). Before testing, mice were acclimatised to the behavioural room. Habituation: mice explored an empty 40 cm × 40 cm × 40 cm arena for 10 min. Training (24 h later): two identical objects were placed and mice explored for 10 min. Testing (1 h later): one familiar object was replaced with a novel object; exploration continued for 5 min. Outcomes (total distance, average speed, number of object-exploration bouts, and time spent exploring novel and familiar objects) were recorded with ANY-MAZE (Stoelting Co., USA). Preference index = A/(A + B) (A: time with the novel object; B: time with the familiar object). Discrimination index = (A − B)/(A + B).

Nissl staining

Cryosections were equilibrated to room temperature and incubated in pre-warmed 0.1% toluidine blue O solution (acetate buffer, pH 4.0) at 60 °C for 10 min. Sections were differentiated in 95% ethanol containing 0.1% acetic acid for 15 s, rinsed, dehydrated through graded ethanol, and cleared in xylene. Sections were mounted with neutral balsam. Bright-field images were captured under identical settings.

SA-β-gal staining

SA-β-gal staining was performed on cells and/or coronal sections using the manufacturer’s kit (pH 6.0). Samples with fresh SA-β-gal staining solution were incubated overnight at 37 °C in a non-CO₂ incubator. Images were acquired on a light microscope. For cells, the percentage of SA-β-gal-positive cells was calculated as (blue-stained/total) × 100%.

Statistical analysis

All experiments were conducted at least in triplicate. Results are presented as mean ± SD and analysed using GraphPad Prism 10. Comparisons among three or more groups were performed using one-way ANOVA followed by Tukey’s post hoc test. p < 0.05 was considered statistically significant.

Results

Effects of SRS11-92 on SH-SY5Y cell viability

To establish an in vitro AD model, SH-SY5Y cells were incubated with Aβ25-35 at 0, 2.5, 5, 10, 20, and 40 μM for 48 h, and viability was assessed using the MTT assay. Compared with control, 20 μM Aβ25-35 reduced viability by approximately 50%, while 40 μM did not cause further significant reduction. Therefore, 20 μM Aβ25-35 was selected for subsequent experiments (p < 0.0001; Fig. 2A). To evaluate SRS11-92 cytotoxicity, cells were treated with 0, 0.25, 0.5, 1, 2, and 4 μM for 48 h. SRS11-92 did not show cytotoxicity up to 1 μM (p > 0.05; Fig. 2B), whereas ≥ 2 μM significantly reduced viability (p < 0.0001; Fig. 2B). Pre-treatment with SRS11-92 (0–4 μM, 4 h) in a dose-dependent manner attenuated Aβ25-35-induced cytotoxicity, with 1 μM showing the most robust protection (p < 0.0001; Fig. 2C). Accordingly, 1 μM was selected as the optimal concentration for SRS11-92 treatment in the following experiments. Morphologically, control cells exhibited normal features with clear boundaries and good adherence. Aβ25-35 caused cellular enlargement and detachment, whereas SRS11-92 restored cell density and morphology in a dose-dependent manner, with 1 μM yielding the clearest rescue (Fig. 2D).

Fig. 2.

Fig. 2

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Effect of Aβ25-35 and SRS11-92 on SH-SY5Y cell viability assessed by MTT assay. A The cytotoxicity of Aβ25-35 in SH-SY5Y cells was studied at various concentrations of Aβ25-35 (0, 2.5, 5, 10, 20, 40 μM) for 48 h (n = 3). B The cytotoxicity of SRS11-92 in SH-SY5Y cells was evaluated at various concentrations of SRS11-92 (0, 0.25, 0.5, 1, 2, 4 μM) for 48 h (n = 3). C Cells pretreated with SRS11-92 (0, 0.25, 0.5, 1, 2, and 4 μM) for 4 h and then exposed to Aβ25-35 (20 μM) for 48 h (n = 3). D Representative images of SH-SY5Y cells in each group were acquired by phase-contrast microscopy (Scale bar: 200 μm). Data are presented as mean ± SD. * p < 0.05, ** p < 0.01, *** p < 0.001 and **** p < 0.0001. #### p < 0.0001 vs. control group

SRS11-92 alleviates Aβ25-35-induced oxidative stress in SH-SY5Y cells

To determine whether SRS11-92 mitigates Aβ25-35-induced oxidative stress, intracellular ROS, MDA, SOD activity, and GSH levels were measured. Aβ25-35 markedly elevated ROS (p < 0.0001; Fig. 3A–B) and MDA (p < 0.01; Fig. 3D), while decreasing SOD activity (p < 0.01; Fig. 3E) and GSH (p < 0.05; Fig. 3C). SRS11-92 pretreatment significantly reduced ROS (p < 0.05; Fig. 3A-B) and MDA (p < 0.05; Fig. 3D) and restored SOD activity (p < 0.05; Fig. 3E) and GSH (p < 0.05; Fig. 3C). These data suggest that SRS11-92 possesses strong antioxidant properties.

Fig. 3.

Fig. 3

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Effect of SRS11-92 on Aβ25-35-induced oxidative stress on SH-SY5Y cells. SH-SY5Y cells were pretreated with SRS11-92 (1 μM) or vehicle for 4 h and subsequently exposed to Aβ25-35 (20 μM) for another 48 h. A Representative images of intracellular ROS accumulation were acquired with a fluorescence microscope in each group (Scale bar: 200 μm). B Fluorescence intensity of ROS was quantified using ImageJ (n = 3). C–E Levels of oxidative stress markers (GSH, MDA, SOD) in SH-SY5Y cells (n = 4). Data are presented as mean ± SD. * p < 0.05, ** p < 0.01, *** p < 0.001 and **** p < 0.0001

SRS11-92 reduces Aβ25-35-induced inflammatory responses in SH-SY5Y cells

Aβ25-35 significantly increased TNF-α (p < 0.001), IL-1β (p < 0.0001), and IL-6 (p < 0.05) (Fig. 4A–C). Pretreatment with SRS11-92 markedly reduced Aβ25-35-induced upregulation of TNF-α (p < 0.05), IL-1β (p < 0.01), and IL-6 (p < 0.05) (Fig. 4A–C), indicating anti-inflammatory activity.

Fig. 4.

Fig. 4

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SRS11-92 decreased Aβ25-35-induced inflammation on SH-SY5Y cells. SH-SY5Y cells were pretreated with SRS11-92 (1 μM) or vehicle for 4 h and subsequently exposed to Aβ25-35 (20 μM) for another 48 h. A–C Relative levels of indicators of inflammation (IL-1β, IL-6 and TNF-α) in SH-SY5Y cells (n = 4). Data are presented as mean ± SD. * p < 0.05, ** p < 0.01, *** p < 0.001 and **** p < 0.0001

SRS11-92 attenuates Aβ25-35-induced cellular senescence in SH-SY5Y cells

SA-β-gal activity and p53, p16, p21 protein levels were examined. Compared with control, the percentage of SA-β-gal-positive cells increased after Aβ25-35 treatment (p < 0.001; Fig. 5A–B). Remarkably, SRS11-92 pretreatment inhibited this increase (p < 0.05; Fig. 5A–B). Aβ25-35 elevated p53 (p < 0.01), p16 (p < 0.001), and p21 (p < 0.001), whereas SRS11-92 downregulated these proteins (p < 0.05; Fig. 5C–F). These findings indicate that SRS11-92 counteracts Aβ25-35-induced cellular senescence.

Fig. 5.

Fig. 5

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SRS11-92 inhibited Aβ25-35-induced cellular senescence on SH-SY5Y cells. SH-SY5Y cells were pretreated with SRS11-92 (1 μM) or vehicle for 4 h and subsequently exposed to Aβ25-35 (20 μM) for another 48 h. A Representative images of SA-β-gal–positive cells in each group were captured by light microscopy. Blue cells were scored as SA-β-gal–positive cells (Scale bar: 100 μm). B The percentage of SA-β-gal-positive cells was quantified using ImageJ (n = 4). C-F The changes in p16, p21 and p53 levels in SH-SY5Y cells were assessed by Western blot and quantified using ImageJ (n = 3). Data are presented as mean ± SD. * p < 0.05, ** p < 0.01 and *** p < 0.001

SRS11-92 modulates the Nrf2/HO-1/NF-κB pathway in SH-SY5Y cells

Western blotting showed that SRS11-92 pretreatment reversed Aβ25-35-induced downregulation of total Nrf2 (p < 0.01) and total HO-1 (p < 0.05) (Fig. 6A, D–E). Nuclear Nrf2 was reduced by Aβ25-35 (p < 0.001; Fig. 6A–B), whereas SRS11-92 increased nuclear accumulation (p < 0.05; Fig. 6A–B), indicating facilitated Nrf2 nuclear translocation and activation. Meanwhile, SRS11-92 inhibited NF-κB p65 nuclear translocation (p < 0.05; Fig. 6A, C). Collectively, these data indicate that SRS11-92 activates Nrf2/HO-1 signalling while suppressing NF-κB activation.

Fig. 6.

Fig. 6

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Effects of SRS11-92 on the Nrf2/HO-1/ NF-κB signalling pathway in Aβ25-35-induced SH-SY5Y cells. A The changes in Nrf2 (nuclear fraction), NF-κB p65 (nuclear fraction), total Nrf2, and total HO-1 levels in SH-SY5Y cells were detected by Western blot, and B–E band intensities were quantified using ImageJ software (n = 3). Data are presented as mean ± SD. *p < 0.05, ** p < 0.01 and *** p < 0.001

Inhibition of Nrf2 reverses the effects of SRS11-92 on Aβ25-35-induced cellular senescence

To confirm the role of Nrf2, ML385 (1 μM) was applied. ML385 (1 μM) blocked SRS11-92-mediated up-regulation of Nrf2 (p < 0.05; Fig. 7A, D) and HO-1 (p < 0.01; Fig. 7A, E), attenuated Nrf2 nuclear accumulation (p < 0.05; Fig. 7A, B), and restored NF-κB p65 nuclear expression (p < 0.05; Fig. 7A, C). Functionally, ML385 reversed SRS11-92 protection, re-elevating p53 (p < 0.05; Fig. 7F, I), p16 (p < 0.01; Fig. 7F, G), and p21 (p < 0.05; Fig. 7F, H) and increasing the percentage of SA-β-gal-positive cells (p < 0.01; Fig. 7J-K). Collectively, these findings confirm that the Nrf2/HO-1/NF-κB axis is required for the anti-senescent action of SRS11-92.

Fig. 7.

Fig. 7

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Inhibition of Nrf2 reversed the effect of SRS11-92 on Aβ25-35-induced cellular senescence in SH-SY5Y cells. A The changes in Nrf2 (nuclear fraction), NF-κB p65 (nuclear fraction), total Nrf2, and total HO-1 levels in SH-SY5Y cells were detected by Western blot, and B–E band intensities were quantified using ImageJ software (n = 3). F The changes in p16, p21 and p53 levels in SH-SY5Y cells were detected by Western blot, and G–I quantitative analysis was completed using ImageJ software (n = 3). J Representative images of SA-β-gal–positive cells in each group were acquired with a light microscope. Blue cells were scored as SA-β-gal–positive cells (Scale bar: 100 μm). K The percentage of SA-β-gal-positive cells was quantified using ImageJ (n = 3). Data are presented as mean ± SD. * p < 0.05 and ** p < 0.01

SRS11-92 ameliorates cognitive impairment, restores neuronal loss, and delays cellular senescence in 3xTg-AD model

To evaluate in vivo efficacy, the NOR test was performed. AD + vehicle mice exhibited significantly lower preference index (p < 0.0001; Fig. 8C) and discrimination index (p < 0.0001; Fig. 8D) than WT + vehicle, while SRS11-92 improved both indices. AD + vehicle mice showed decreased distance travelled, average speed and novel-object exploration bouts (Fig. 8E–G), and SRS11-92 increased novel-object exploration bouts (p < 0.05; Fig. 8G). Nissl staining showed that in WT + vehicle cortices, normal neurons showed loose chromatin and prominent nucleoli (Fig. 9A). In the AD + vehicle, Nissl-positive neurons were reduced compared with WT + vehicle (p < 0.0001), and this reduction was partially rescued by SRS11-92 (p < 0.05) (Fig. 9A). Moreover, AD + SRS11-92 mice displayed a decreased SA-β-gal-positive burden in the hippocampus compared with age-matched AD + vehicle mice (Fig. 9B). Collectively, these results demonstrate that SRS11-92 improves cognitive performance, attenuates neuronal loss, and reduces cellular senescence in 3xTg-AD mice, consistent with in vitro protection.

Fig. 8.

Fig. 8

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SRS11-92 ameliorated cognitive impairment in 3xTg-AD model. A Representative images of exploration tracks in each group. B Representative images of heatmaps in each group. C Preference index. D Discrimination index. E Total distance. F Average speed. G Number of exploration bouts for the novel object. H Number of exploration bouts for the familiar object. Data are presented as mean ± SD. n = 8–11 mice per group, * p < 0.05, ** p < 0.01 and **** p < 0.0001

Fig. 9.

Fig. 9

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SRS11-92 partially rescued neuronal counts, and delayed cellular senescence in 3 × Tg-AD mice. A Representative images of cortical Nissl staining in each group (Scale bar: 100 μm) and Nissl-positive neurons were quantified using ImageJ (n = 3). B Representative images of hippocampal SA-β-gal–positive burden in each group. Data are presented as mean ± SD. * p < 0.05 and **** p < 0.0001

Discussion

AD is increasingly recognised as a disorder in which oxidative stress, sterile inflammation, and cellular senescence intersect to drive neurodegeneration (Wyss-Coray 2006; Chinta et al. 2018; Masaldan et al. 2019; Zhang et al. 2014). This study shows that SRS11-92 mitigates Aβ25-35-evoked oxidative stress, suppresses pro-inflammatory cytokines, and attenuates senescence phenotypes in SH-SY5Y cells. Mechanistically, SRS11-92 activates the Nrf2/HO-1 axis and limits NF-κB p65 nuclear translocation; the Nrf2 inhibitor ML385 abrogates these molecular and phenotypic benefits, indicating that the anti-senescent effect of SRS11-92 is Nrf2-dependent. Extending these findings in vivo, SRS11-92 improves cognitive function in 3xTg-AD mice and partially rescues cortical neuronal loss while reducing hippocampal SA-β-gal-positive area. Taken together, these findings identify SRS11-92 as a candidate modulator of the Nrf2/HO-1/NF-κB network with convergent antioxidant, anti-inflammatory, and anti-senescent actions.

Increased senescent cells have also been observed in multiple transgenic AD models such as APP/PS1, 3xFAD, and 5xFAD mice (Zhang et al. 2019; Hu et al. 2021; Xie et al. 2021; Hou et al. 2021). Pharmacological clearance of senescent cells using senolytic agents reduces Aβ plaque burden and improves cognitive deficits (Zhang et al. 2019; Gonzales et al. 2023). Consistent with these studies, Aβ exposure is sufficient to induce senescence-like features in neuronal cells, including upregulated cyclin-dependent kinase inhibitor 2A (CDKN2A/p16), cyclin-dependent kinase inhibitor 1A (CDKN1A/p21) and SASP production (Zhang et al. 2019; Wang et al. 2023; Wang et al. 2021). Based on this evidence, we treated SH-SY5Y cells with Aβ25-35 to mimic the pathological state of AD-related neuronal senescence. Aβ25-35 increased oxidative burden and neuronal senescence, whereas SRS11-92 countered both the initiating (oxidative stress) and downstream (inflammatory/SASP-like) components. Therefore, coordinated reduction in oxidative stress and inflammatory mediators provides a plausible mechanistic bridge to the observed decline in senescence markers.

Senescent cells are characterised by permanent cell-cycle arrest, resistance to apoptosis, and activation of the DNA damage response, often accompanied by the SASP (Zhu et al. 2015). These cells typically exhibit enlarged morphology and lysosomal expansion, reflected by increased SA-β-gal activity (Campisi and d’Adda Fagagna 2007; Hernandez-Segura et al. 2018; Khosla et al. 2020). CDKN2A/p16 inhibits CDK4 and CDK6, arresting the cell cycle in G1 phase and preventing progression into S phase, thereby promoting senescence (Luo et al. 2018; Yang et al. 2017). Recent evidence indicates that Aβ-induced oxidative stress triggers DNA damage, activates p53 and p21, and results in canonical features of senescence, including elevated intracellular ROS and cell-cycle arrest (Micco et al. 2021). Here, SRS11-92 downregulated p16, p53, and p21 in Aβ25-35-treated SH-SY5Y cells, suggesting anti-senescence effects by modulating cell-cycle control. Further work is needed to determine the specific arrest phase induced by oligomeric Aβ in SH-SY5Y cells, thereby clarifying how these markers contribute to neuronal senescence (Jacobs et al. 2000).

Nrf2 is a master regulator of redox homeostasis (Gao et al. 2017). Its expression declines with ageing (O’Rourke et al. 2024) and is reduced in aged or AD brain tissue (Silva-Palacios et al. 2018; Bahn and Jo 2019). Under chronic inflammation or oxidative stress, activated Nrf2 translocates to the nucleus, binds AREs, and induces target genes such as HO-1, NQO1, SOD, glutathione peroxidases (GPx), ferritin, and sulphoxide-related enzymes, coordinating adaptive responses and conferring cytoprotection (Dinkova-Kostova et al. 2018). HO-1 is the most canonical downstream target of Nrf2 (Chen-Roetling and Regan 2017). Activation of the Nrf2/HO-1 pathway can attenuate cellular senescence by reducing SASP and enhancing senescence surveillance (O’Rourke et al. 2024). NF-κB regulates the expression of SASP-related genes in senescent cells (Salminen et al. 2012). The SASP releases pro-inflammatory chemokines, cytokines, and metalloproteinases that affect neighbouring cells in a paracrine manner, accelerating ageing and forming a self-reinforcing cycle (Melo Dos Santos et al. 2024; Terao et al. 2022). ROS can activate NF-κB, causing p65 nuclear translocation and phosphorylation and enhancing SASP production (Liu et al. 2008; Kim et al. 2013). Nrf2 can restrain NF-κB in part via up-regulating HO-1 and antioxidant defences, thereby improving redox status and limiting ROS-mediated NF-κB activation (Ganesh Yerra et al. 2013; Wu et al. 2023; Luo et al. 2017). Here, SRS11-92 restored total Nrf2 and HO-1 levels and promoted Nrf2 nuclear accumulation while repressing NF-κB p65 nuclear translocation (Fig. 10). Nrf2 blockade with ML385 reversed these effects and re-elevated senescence markers, supporting a mechanism whereby SRS11-92 acts through Nrf2/HO-1 to constrain NF-κB-linked inflammatory signalling and senescence.

Fig. 10.

Fig. 10

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Proposed mechanism by which SRS11-92 mitigates oxidative stress-induced cellular senescence. SRS11-92 may enter cells and act directly as antioxidant and anti-senescence agent, promoting activation of Nrf2/HO-1 axis. Activated Nrf2 migrates to the nucleus, where it enhances antioxidant defences and HO-1 expression, thereby neutralizing ROS and detoxifying electrophiles, which in turn reduces ROS-mediated NF-κB activation by limiting NF-κB (p65) nuclear translocation and IκBα phosphorylation. As ROS generation decreases and antioxidant defences are upregulated, oxidative stress–induced cellular senescence is attenuated. Aβ, amyloid-β; Nrf2, nuclear factor erythroid 2-related factor 2; HO-1, haem oxygenase-1; NF-κB, Nuclear factor kappa-B; NF-κB (p65), RelA subunit of NF-κB; ROS, reactive oxygen species; GSH, glutathione; SOD, superoxide dismutase; IκBα, inhibitor of kappa-B alpha; SASP, senescence-associated secretory phenotype; ARE, antioxidant response element

This work demonstrates that SRS11-92 exhibits anti-ageing, antioxidant effects, and cognition-improving effects in AD models, with potential translational relevance. Beyond direct Aβ exposure, behavioural and histological benefits in 3xTg-AD mice support targeting redox–inflammation–senescence crosstalk. In the NOR test, SRS11-92 improved preference and discrimination indices, consistent with enhanced cognitive function. Concordantly, cortical neuronal loss was partially rescued and hippocampal SA-β-gal burden was reduced. Additionally, these findings position Nrf2-centric modulation as a promising strategy to interrupt the self-amplifying loop linking redox imbalance, SASP, and neurodegeneration, and support further translational and clinical development of SRS11-92. Future work should refine efficacy of intervention timings and sexes on the results to more fully understand the mechanism of action of this drug. Long-term efficacy, safety, and adverse effects require comprehensive preclinical assessment and adequately powered clinical trials.

Conclusion

SRS11-92 confers multi-level protection in AD models by activating Nrf2/HO-1 and constraining NF-κB signalling, thereby reducing oxidative stress, inflammation, and cellular senescence.

Abbreviations

Aβ

Amyloid-beta

AD

Alzheimer’s disease

ARE

Antioxidant response element

CDKN2A

Cyclin-dependent kinase inhibitor 2A

ELISA

Enzyme-linked immunosorbent assay

GPx

Glutathione peroxidases

GSH

Glutathione

HO-1

Hemeoxygenase-1

IL-1β

Interleukin-1 beta

IL-6

Interleukin-6

MDA

Malondialdehyde

NF-κB

Nuclear factor kappa-B

NFT

Neurofibrillary tangles

Nrf2

Nuclear factor erythroid 2-related factor 2

PBS

Phosphate-buffered saline

ROS

Reactive oxygen species

SASP

Senescence-associated secretory phenotype

SA-β-gal

Senescence-associated β- galactosidase

SOD

Superoxide dismutase

TBS

Tris-buffer saline

TNF-α

Tumour necrosis factor-alpha

Author contributions

Y.G. contributed to study design, data interpretation, and writing—original draft. Y. G., H.C. and C.Z. contributed to the literature search and resources, methodology. Y.H., Z.G., Y.S. and X.C. contributed to data analyses and figures. Q.J and F.W contributed to conceptualization, study design, methodology, supervision, validation, and writing—review & editing.

Funding

This work was funded by the National Key, Research and Development Programme of Hubei Province [2020BCA089], the National Natural Science Foundation of China [81974218].

Data availability

The data that support the findings of this study are available from the corresponding author (F.W.) upon reasonable request.

Declarations

Conflict of interest

The authors have no relevant financial or non-financial interests to disclose.

Ethical approval

All animal experiments were conducted in accordance with the guidelines approved by the Committee on the Ethics of Animal Experiments and the Institutional Animal Care and Use Committee at Tongji hospital, Tongji Medical College, Huazhong University of Science and Technology.

Consent for publication

Not applicable.

Footnotes

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Contributor Information

Qingqing Jiang, Email: 15926273940@163.com.

Furong Wang, Email: wangfurong.china@163.com.

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Associated Data

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Data Availability Statement

The data that support the findings of this study are available from the corresponding author (F.W.) upon reasonable request.

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