Emerging Immunotherapy Approaches for Treating Prostate Cancer.

Immunotherapy has emerged as an important approach for cancer treatment, but its clinical efficacy has been limited in prostate cancer compared to other malignancies. This review summarizes key immunotherapy strategies under evaluation for prostate cancer, including immune checkpoint inhibitors, bispecific T cell-engaging antibodies, chimeric antigen receptor (CAR) T cells, therapeutic vaccines, and cytokines. For each modality, the rationale stemming from preclinical studies is discussed along with outcomes from completed clinical trials and strategies to improve clinical efficacy that are being tested in ongoing clinical trials. Imperative endeavors include biomarker discovery for patient selection, deciphering resistance mechanisms, refining cellular therapies such as CAR T cells, and early-stage intervention were reviewed. These ongoing efforts instill optimism that immunotherapy may eventually deliver significant clinical benefits and expand treatment options for patients with advanced prostate cancer.

Comparison of Homo-Polyimide Films Derived from Two Isomeric Bis-Benzimidazole Diamines.

Heteroaromatic polyimides (PIs) containing benzimidazole have attracted tremendous attention due to their positive impact on the properties of PIs. Some research on PIs containing 4,4'-[5,5'-bi-1H-benzimidazole]-2,2'-diylbis-benzenamine (4-AB) has been reported. However, reports are lacking on homo-polyimides (homo-PIs) containing 3,3'-[5,5'-bi-1H-benzimidazole]-2,2'-diylbis-benzenamine (3-AB), which is one of the isomers of 4-AB. In this paper, the influence of amino groups' positions on the performance of homo-PIs was investigated. It was found that the net charge of the amine N group in 4-AB was lower than that of 3-AB, resulting in higher reactivity of 4-AB. Consequently, PIs containing 4-AB displayed better mechanical performance. Molecular simulation confirmed that 3-AB and its corresponding PI chain exhibited distorted conformation, leading to the PI films containing 3-AB having a lighter color. In addition, the 3-AB structure was calculated to have higher rotational energy compared to 4-AB, resulting in a higher glass transition temperature (Tg) in PIs prepared from 3-AB. On the other hand, PIs containing 4-AB exhibited a higher level of molecular linearity, leading to a lower coefficient of thermal expansion (CTE) compared to PIs prepared from 3-AB. Furthermore, all PIs showed higher thermal stability with a 5% weight loss temperature above 530 °C and Tg higher than 400 °C.

Research progress on mechanism and imaging of temporal lobe injury induced by radiotherapy for head and neck cancer.

Radiotherapy (RT) is an effective treatment for head and neck cancer (HNC). Radiation-induced temporal lobe injury (TLI) is a serious complication of RT. Late symptoms of radiation-induced TLI are irreversible and manifest as memory loss, cognitive impairment, and even temporal lobe necrosis (TLN). It is currently believed that the mechanism of radiation-induced TLI involves microvascular injury, neuron and neural stem cell injury, glial cell damage, inflammation, and the production of free radicals. Significant RT-related structural changes and dose-dependent changes in gray matter (GM) and white matter (WM) volume and morphology were observed through computed tomography (CT) and magnetic resonance imaging (MRI) which were common imaging assessment tools. Diffusion tensor imaging (DTI), dispersion kurtosis imaging (DKI), susceptibility-weighted imaging (SWI), resting-state functional magnetic resonance (rs-fMRI), magnetic resonance spectroscopy (MRS), and positron emission tomography (PET) can be used for early diagnosis and prognosis evaluation according to functional, molecular, and cellular processes of TLI. Early diagnosis of TLI is helpful to reduce the incidence of TLN and its related complications. This review summarizes the clinical features, mechanisms, and imaging of radiation-induced TLI in HNC patients. KEY POINTS: • Radiation-induced temporal lobe injury (TLI) is a clinical complication and its symptoms mainly include memory impairment, headache, and cognitive impairment. • The mechanisms of TLI include microvascular injury, cell injury, and inflammatory and free radical injury. Significant RT-related structural changes and dose-dependent changes in TL volume and morphology were observed through CT and MRI. • SWI, MRS, DTI, and DKI and other imaging examinations can detect anatomical and functional, molecular, and cellular changes of TLI.

Sulforaphane prevents angiotensin II-induced cardiomyopathy by activation of Nrf2 through epigenetic modification.

Nuclear factor erythroid 2-related factor (Nrf2) is an important regulator of cellular antioxidant defence. We previously showed that SFN prevented Ang II-induced cardiac damage via activation of Nrf2. However, the underlying mechanism of SFN's persistent cardiac protection remains unclear. This study aimed to explore the potential of SFN in activating cardiac Nrf2 through epigenetic mechanisms. Wild-type mice were injected subcutaneously with Ang II, with or without SFN. Administration of chronic Ang II-induced cardiac inflammatory factor expression, oxidative damage, fibrosis and cardiac remodelling and dysfunction, all of which were effectively improved by SFN treatment, coupled with an up-regulation of Nrf2 and downstream genes. Bisulfite genome sequencing and chromatin immunoprecipitation (ChIP) were performed to detect the methylation level of the first 15 CpGs and histone H3 acetylation (Ac-H3) status in the Nrf2 promoter region, respectively. The results showed that SFN reduced Ang II-induced CpG hypermethylation and promoted Ac-H3 accumulation in the Nrf2 promoter region, accompanied by the inhibition of global DNMT and HDAC activity, and a decreased protein expression of key DNMT and HDAC enzymes. Taken together, SFN exerts its cardioprotective effect through epigenetic modification of Nrf2, which may partially contribute to long-term activation of cardiac Nrf2.

The role of short-chain fatty acids in intestinal barrier function, inflammation, oxidative stress, and colonic carcinogenesis.

Short-chain fatty acids (SCFAs), mainly including acetate, propionate, and butyrate, are metabolites produced during the bacterial fermentation of dietary fiber in the intestinal tract. They are believed to be essential factors affecting host health. Most in vitro and ex vivo studies have shown that SCFAs affect the regulation of inflammation, carcinogenesis, intestinal barrier function, and oxidative stress, but convincing evidence in humans is still lacking. Two major SCFA signaling mechanisms have been identified: promotion of histone acetylation and activation of G-protein-coupled receptors. In this review, we introduce the production and metabolic characteristics of SCFAs, summarize the potential effects of SCFAs on the four aspects mentioned above and the possible mechanisms. SCFAs have been reported to exert a wide spectrum of positive effects and have a high potential for therapeutic use in human-related diseases.

Efficacy and safety of systemic treatments for patients with recurrent/metastatic head and neck squamous cell carcinoma: A systematic review and network meta-analysis.

A variety of systemic chemotherapy regimens have been used for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). However, most guidelines have been derived from a single clinical trial, and no studies have comprehensively compared their efficacy and safety. We systematically searched PubMed, Embase, Web of Science, and Cochrane Library databases. Eligible studies reported overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and ≥ 3 adverse events rate (AEs). Eighteen eligible trials involving 4930 patients and 15 treatment regimens were included. The results suggest that patients with R/M HNSCC exhibit better tumor response with the cetuximab/platinum/5-FU, pembrolizumab/platinum/5-FU or pembrolizumab alone, accompanied by a low AE rate. Nivolumab also showed better efficacy than other single agents. Immunotherapy has achieved better efficacy.

First case of AML with rare chromosome translocations: a case report of twins.

BACKGROUND: Leukemia is different from solid tumor by harboring genetic rearrangements that predict prognosis and guide treatment strategy. PML-RARA, RUNX1-RUNX1T1, and KMT2A-rearrangement are common genetic rearrangements that drive the development of acute myeloid leukemia (AML). By contrast, rare genetic rearrangements may also contribute to leukemogenesis but are less summarized. CASE PRESENTATION: Here we reported rare fusion genes ZNF717-ZNF37A, ZNF273-DGKA, and ZDHHC2-TTTY15 in a 47-year-old AML-M4 patient with FLT3 internal tandem duplication (ITD) discovered by whole genome sequencing (WGS) using the patient's healthy sibling as a sequencing control. CONCLUSION: This is, to our knowledge, the first case of AML with fusion gene ZNF717-ZNF37A, ZNF273-DGKA, and ZDHHC2-TTTY15.

Therapeutic potential of PACAP for neurodegenerative diseases.

Pituitary adenylate cyclase activating polypeptide (PACAP) is widely expressed in the central and peripheral nervous system. PACAP can initiate multiple signaling pathways through binding with three class B G-protein coupled receptors, PAC1, VPAC1 and VPAC2. Previous studies have revealed numerous biological activities of PACAP in the nervous system. PACAP acts as a neurotransmitter, neuromodulator and neurotrophic factor. Recently, its neuroprotective potential has been demonstrated in numerous in vitro and in vivo studies. Furthermore, evidence suggests that PACAP might move across the blood-brain barrier in amounts sufficient to affect the brain functions. Therefore, PACAP has been examined as a potential therapeutic method for neurodegenerative diseases. The present review summarizes the recent findings with special focus on the models of Alzheimer's disease (AD) and Parkinson's disease (PD). Based on these observations, the administered PACAP inhibits pathological processes in models of AD and PD, and alleviates clinical symptoms. It thus offers a novel therapeutic approach for the treatment of AD and PD.

Role of neurotrophin in the taste system following gustatory nerve injury.

Taste system is a perfect system to study degeneration and regeneration after nerve injury because the taste system is highly plastic and the regeneration is robust. Besides, degeneration and regeneration can be easily measured since taste buds arise in discrete locations, and nerves that innervate them can be accurately quantified. Neurotrophins are a family of proteins that regulate neural survival, function, and plasticity after nerve injury. Recent studies have shown that neurotrophins play an important role in the developmental and mature taste system, indicating neurtrophin might also regulate taste system following gustatory nerve injury. This review will summarize how taste system degenerates and regenerates after gustatory nerve cut and conclude potential roles of neurotrophin in regulating the process.

TAM receptor deficiency affects adult hippocampal neurogenesis.

The Tyro3, Axl and Mertk (TAM) subfamily of receptor protein tyrosine kinases functions in cell growth, differentiation, survival, and most recently found, in the regulation of immune responses and phagocytosis. All three receptors and their ligands, Gas6 (growth arrest-specific gene 6) and protein S, are expressed in the central nervous system (CNS). TAM receptors play pivotal roles in adult hippocampal neurogenesis. Loss of these receptors causes a comprised neurogenesis in the dentate gyrus of adult hippocampus. TAM receptors have a negative regulatory effect on microglia and peripheral antigen-presenting cells, and play a critical role in preventing overproduction of pro-inflammatory cytokines detrimental to the proliferation, differentiation, and survival of adult neuronal stem cells (NSCs). Besides, these receptors also play an intrinsic trophic function in supporting NSC survival, proliferation, and differentiation into immature neurons. All these events collectively ensure a sustained neurogenesis in adult hippocampus.

AdipoRon promotes amyloid-ß clearance through enhancing autophagy via nuclear GAPDH-induced sirtuin 1 activation in Alzheimer's disease.

BACKGROUND AND PURPOSE: Amyloid-ß (Aß) peptide is one of the more important pathological markers in Alzheimer's disease (AD). The development of AD impairs autophagy, which results in an imbalanced clearance of Aß. Our previous research demonstrated that AdipoRon, an agonist of adiponectin receptors, decreased the deposition of Aß and enhanced cognitive function in AD. However, the exact mechanisms by which AdipoRon affects Aß clearance remain unclear. EXPERIMENTAL APPROACH: We studied how AdipoRon affects autophagy in HT22 cells and APP/PS1 transgenic mice. We also investigated the signalling pathway involved and used pharmacological inhibitors to examine the role of autophagy in this process. KEY RESULTS: AdipoRon promotes Aß clearance by activating neuronal autophagy in the APP/PS1 transgenic mice. Interestingly, we found that AdipoRon induces the nuclear translocation of GAPDH, where it interacts with the SIRT1/DBC1 complex. This interaction then leads to the release of DBC1 and the activation of SIRT1, which in turn activates autophagy. Importantly, we found that inhibiting either GAPDH or SIRT1 to suppress the activity of SIRT1 counteracts the elevated autophagy and decreased Aß deposition caused by AdipoRon. This suggests that SIRT1 plays a critical role in the effect of AdipoRon on autophagic induction in AD. CONCLUSION AND IMPLICATIONS: AdipoRon promotes the clearance of Aß by enhancing autophagy through the AdipoR1/AMPK-dependent nuclear translocation of GAPDH and subsequent activation of SIRT1. This novel molecular pathway sheds light on the modulation of autophagy in AD and may lead to the development of new therapeutic strategies targeting this pathway.

The Pivotal Role of Benzimidazole in Improving the Thermal and Dielectric Performance of Upilex-Type Polyimide.

Polyimide (PI) with ultra-high thermal resistance and stability is essential for application as a flexible substrate in electronic devices. Here, the Upilex-type polyimides, which contained flexibly "twisted" 4,4'-oxydianiline (ODA), have achieved various performance improvements via copolymerization with a diamine containing benzimidazole structure. With the rigid benzimidazole-based diamine bearing conjugated heterocyclic moieties and hydrogen bond donors fused into the PI backbone, the benzimidazole-containing PI showed outstanding thermal, mechanical, and dielectric performance. Specifically, the PI containing 50% bis-benzimidazole diamine achieved a 5% decomposition temperature at 554 °C, an excellent high glass transition temperature of 448 °C, and a coefficient of thermal expansion lowered to 16.1 ppm/K. Meanwhile, the tensile strength and modulus of the PI films containing 50% mono-benzimidazole diamine increased to 148.6 MPa and 4.1 GPa, respectively. Due to the synergistic effect of rigid benzimidazole and hinged, flexible ODA, all PI films exhibited an elongation at break above 4.3%. The electrical insulation of the PI films was also improved with a dielectric constant lowered to 1.29. In summary, with appropriate mixing of rigid and flexible moieties in the PI backbone, all the PI films showed superior thermal stability, excellent flexibility, and acceptable electrical insulation.

Enhanced Efficacy of Chemotherapy by Addition of Immune Checkpoint Inhibitors in Stage IV Large Cell Neuroendocrine Carcinoma of the Lung: A Real-World Analysis.

Background: Large Cell Neuroendocrine Carcinoma (LCNEC) is a high-grade malignancy with limited treatment options. Despite promising results of immunotherapy in non-small cell and small cell lung cancers, its benefit in LCNEC remains elusive. Methods: We included 24 patients diagnosed with stage IV LCNEC from the Moffitt Cancer Center database who received systemic therapy between January 2016 and May 2021. Group A comprised patients who received first-line CT and ICI (anti-PD-1 or anti-PD-L1 therapy for ICI, n = 11), and Group B received first-line CT only (n = 13). The collected data encompassed overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and toxicities since treatment initiation. Results: Kaplan-Meier survival analysis revealed median OS was 56 weeks (95%CI = 22.2-89.8) and 28 weeks (95% CI=16.3-39.7) in groups A and B, respectively. Log-rank test showed the difference was statistically significant (p=0.029). Median PFS was 32 weeks (95%CI=14.7-49.3) in group A and 20 weeks (95% CI=13.8-26.2) in groups B, but the difference was not statistically significant (p= 0.136). Univariate Cox analysis confirmed that the addition of ICI to CT significantly improved OS in patients with stage IV LCNEC (HR=0.35, 95% CI=0.13-0.95, p = 0.039). The ORR (63.6% vs 45.4%, p= 0.670) and DCR (81.8% vs 63.6%, p= 0.635) tended to be higher in group A than in group B but the difference was not statistically significant. Importantly, the combined treatment demonstrated a satisfactory safety profile, with only two patients reporting grade 2 or higher adverse events. Conclusions: Our results suggest that the combination of immunotherapy with chemotherapy holds potential for improving outcomes in stage IV LCNEC. Despite the retrospective nature and limited sample size of our study, these preliminary findings provide a valuable insight into the potential of immunotherapy in LCNEC treatment and encourage further research through larger, prospective trials.

Overcoming acquired resistance to cancer immune checkpoint therapy: potential strategies based on molecular mechanisms.

Immune checkpoint inhibitors (ICIs) targeting CTLA-4 and PD-1/PD-L1 to boost tumor-specific T lymphocyte immunity have opened up new avenues for the treatment of various histological types of malignancies, with the possibility of durable responses and improved survival. However, the development of acquired resistance to ICI therapy over time after an initial response remains a major obstacle in cancer therapeutics. The potential mechanisms of acquired resistance to ICI therapy are still ambiguous. In this review, we focused on the current understanding of the mechanisms of acquired resistance to ICIs, including the lack of neoantigens and effective antigen presentation, mutations of IFN-γ/JAK signaling, and activation of alternate inhibitory immune checkpoints, immunosuppressive tumor microenvironment, epigenetic modification, and dysbiosis of the gut microbiome. Further, based on these mechanisms, potential therapeutic strategies to reverse the resistance to ICIs, which could provide clinical benefits to cancer patients, are also briefly discussed.

Emerging Immunotherapy Approaches for Advanced Clear Cell Renal Cell Carcinoma.

The most common subtype of renal cell carcinoma is clear cell renal cell carcinoma (ccRCC). While localized ccRCC can be cured with surgery, metastatic disease has a poor prognosis. Recently, immunotherapy has emerged as a promising approach for advanced ccRCC. This review provides a comprehensive overview of the evolving immunotherapeutic landscape for metastatic ccRCC. Immune checkpoint inhibitors (ICIs) like PD-1/PD-L1 and CTLA-4 inhibitors have demonstrated clinical efficacy as monotherapies and in combination regimens. Combination immunotherapies pairing ICIs with antiangiogenic agents, other immunomodulators, or novel therapeutic platforms such as bispecific antibodies and chimeric antigen receptor (CAR) T-cell therapy are areas of active research. Beyond the checkpoint blockade, additional modalities including therapeutic vaccines, cytokines, and oncolytic viruses are also being explored for ccRCC. This review discusses the mechanisms, major clinical trials, challenges, and future directions for these emerging immunotherapies. While current strategies have shown promise in improving patient outcomes, continued research is critical for expanding and optimizing immunotherapy approaches for advanced ccRCC. Realizing the full potential of immunotherapy will require elucidating mechanisms of response and resistance, developing predictive biomarkers, and rationally designing combination therapeutic regimens tailored to individual patients. Advances in immunotherapy carry immense promise for transforming the management of metastatic ccRCC.

Association of Age With Treatment-Related Adverse Events and Survival in Patients With Metastatic Colorectal Cancer.

Importance: While the incidence of early-onset metastatic colorectal cancer (mCRC) has been increasing, studies on the age-related disparity in this group of patients are limited. Objective: To evaluate the association of age with treatment-related adverse events and survival in patients with mCRC and explore the potential underlying factors. Design, Setting, and Participants: This cohort study included 1959 individuals. Individual data on 1223 patients with mCRC who received first-line fluorouracil and oxaliplatin therapy in 3 clinical trials, and clinical and genomic data of 736 patients with mCRC from Moffitt Cancer Center were used to assess genomic alterations and serve as an external validation cohort. All statistical analyses were conducted from October 1, 2021, through November 12, 2022. Exposures: Metastatic colorectal cancer. Main Outcomes and Measures: Survival outcomes and treatment-related adverse events were compared among patients in 3 age groups: younger than 50 (early onset), 50 to 65, and older than 65 years. Results: In the total population of 1959 individuals, 1145 (58.4%) were men. Among 1223 patients from previous clinical trials, 179 (14.6%) in the younger than 50 years group, 582 (47.6%) in the 50 to 65 years group, and 462 (37.8%) in the older than 65 years group had similar baseline characteristics except for sex and race. The younger than 50 years group had significantly shorter progression-free survival (PFS) (hazard ratio [HR], 1.46; 95% CI, 1.22-1.76; P < .001) and overall survival (OS) (HR, 1.48; 95% CI, 1.19-1.84; P < .001) compared with the 50 to 65 years group after adjustment for sex, race, and performance status. Significantly shorter OS in the younger than 50 years group was confirmed in the Moffitt cohort. The younger than 50 years group had a significantly higher incidence of nausea and vomiting (69.3% vs 57.6% [50-65 years] vs 60.4% [>65 years]; P = .02), severe abdominal pain (8.4% vs 3.4% vs 3.5%; P = .02), severe anemia (6.1% vs 1.0% vs 1.5%; P < .001), and severe rash (2.8% vs 1.2% vs 0.4% P = .047). The younger than 50 years group also had earlier onset of nausea and vomiting (1.0 vs 2.1 vs 2.6 weeks; P = .01), mucositis (3.6 vs 5.1 vs 5.7 weeks; P = .05), and neutropenia (8.0 vs 9.4 vs 8.4 weeks; P = .04), and shorter duration of mucositis (0.6 vs 0.9 vs 1.0 weeks; P = .006). In the younger than 50 years group, severe abdominal pain and severe liver toxic effects were associated with shorter survival. The Moffitt genomic data showed that the younger than 50 years group had a higher prevalence of CTNNB1 mutation (6.6% vs 3.1% vs 2.3%; P = .047), ERBB2 amplification (5.1% vs 0.6% vs 2.3%; P = .005), and CREBBP mutation (3.1% vs 0.9% vs 0.5%; P = .05), but lower prevalence of BRAF mutation (7.7% vs 8.5% vs 16.7%; P = .002). Conclusions and Relevance: In this cohort study of 1959 patients, those with early-onset mCRC showed worse survival outcomes and unique adverse event patterns, which could be partially attributed to distinct genomic profiles. These findings may inform individualized management approaches in patients with early-onset mCRC.

Prospective Application of Ferroptosis in Hypoxic Cells for Tumor Radiotherapy.

Radiation therapy plays an increasingly important role in cancer treatment. It can inhibit the progression of various cancers through radiation-induced DNA breakage and reactive oxygen species (ROS) overload. Unfortunately, solid tumors, such as breast and lung cancer, often develop a hypoxic microenvironment due to insufficient blood supply and rapid tumor proliferation, thereby affecting the effectiveness of radiation therapy. Restraining hypoxia and improving the curative effect of radiotherapy have become difficult problems. Ferroptosis is a new type of cell death caused by lipid peroxidation due to iron metabolism disorders and ROS accumulation. It plays an important role in both hypoxia and radiotherapy and can enhance the radiosensitivity of hypoxic tumor cells by amplifying oxidative stress or inhibiting antioxidant regulation. In this review, we summarize the internal relationship and related mechanisms between ferroptosis and hypoxia, thus exploring the possibility of inducing ferroptosis to improve the prognosis of hypoxic tumors.

ARTS, an unusual septin, regulates tumorigenesis by promoting apoptosis.

Apoptosis plays particularly important roles in tumorigenesis through various mechanisms. Apoptosis can be initiated by both extrinsic and intrinsic signals centered in and coming from the mitochondria. Antiapoptotic proteins promote tumor progression, and the occurrence and progression of tumors are closely related to antiapoptotic protein expression. As the only member of the septin gene family with proapoptotic function, apoptosis-related proteins in the TGF-ß signaling pathway (ARTS) has received extensive attention for its unique structure. In contrast, unlike other known inhibitors of apoptosis protein (IAP) antagonists, ARTS exhibits a stronger tumor suppressor potential. Recent research has shown that ARTS can bind and inhibit XIAP and Bcl-2 directly or assist p53 in the degradation of Bcl-XL. Here, we review recent advances in the molecular mechanisms by which the proapoptotic protein ARTS, with its unique structure, inhibits tumorigenesis. We also discuss the possibility of mimicking ARTS to develop small-molecule drugs.

Potential targets and treatments affect oxidative stress in gliomas: An overview of molecular mechanisms.

Oxidative stress refers to the imbalance between oxidation and antioxidant activity in the body. Oxygen is reduced by electrons as part of normal metabolism leading to the formation of various reactive oxygen species (ROS). ROS are the main cause of oxidative stress and can be assessed through direct detection. Oxidative stress is a double-edged phenomenon in that it has protective mechanisms that help to destroy bacteria and pathogens, however, increased ROS accumulation can lead to host cell apoptosis and damage. Glioma is one of the most common malignant tumors of the central nervous system and is characterized by changes in the redox state. Therapeutic regimens still encounter multiple obstacles and challenges. Glioma occurrence is related to increased free radical levels and decreased antioxidant defense responses. Oxidative stress is particularly important in the pathogenesis of gliomas, indicating that antioxidant therapy may be a means of treating tumors. This review evaluates oxidative stress and its effects on gliomas, describes the potential targets and therapeutic drugs in detail, and clarifies the effects of radiotherapy and chemotherapy on oxidative stress. These data may provide a reference for the development of precise therapeutic regimes of gliomas based on oxidative stress.

Essential role of Nrf2 in sulforaphane-induced protection against angiotensin II-induced aortic injury.

AIMS: Cardiovascular disease (CVD) is the leading cause of death worldwide. Inflammation and oxidative stress are the primary factors underlying angiotensin II (Ang II)-induced aortic damage. Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important antioxidative stress factor. Sulforaphane (SFN), which is naturally found in cruciferous vegetables, is an Nrf2 agonist that is safe for oral administration. Here, we aimed to explore the potential of SFN in protecting against Ang II-induced aortic damage by upregulating Nrf2 expression via the extracellular signal-regulated kinase (ERK)/glycogen synthase kinase-3 beta (GSK-3ß)/Fyn pathway. MAIN METHODS AND KEY FINDINGS: Wild-type (WT) C57BL/6J and Nrf2-knockout (Nrf2-KO) mice were injected with Ang II to induce aortic inflammation, oxidative stress, and cardiac remodeling (increased fibrosis and wall thickness). SFN treatment prevented aortic damage via Nrf2 activation in the WT mice. However, the protective effect of SFN on Ang II-induced aortic damage and upregulation of genes downstream of Nrf2 were not observed in Nrf2-KO mice. SFN induced the upregulation of aortic Nrf2 and inhibited the accumulation of ERK, GSK-3ß, and Fyn in the nuclei. SIGNIFICANCE: These results revealed that Nrf2 plays a central role in protecting against Ang II-induced aortic injury. Furthermore, SFN prevented Ang II-induced aortic damage by activating Nrf2 through the ERK/GSK-3ß/Fyn pathway.