Tier 2 — strong

Sulforaphane — a compound with potential health benefits for disease prevention and treatment: insights from pharmacological and toxicological experimental studies

Baralić K, Živanović J, Marić Đ, Bozic D, Grahovac L, Antonijević Miljaković E, Ćurčić M, Buha Djordjevic A, Bulat Z, Antonijević B, Đukić-Ćosić D

Antioxidants 2024 Volume 13, Issue 2, article 147

Bibliography

DOI: 10.3390/antiox13020147
PubMed: PMID 38397745
PubMed Central: PMC10886109
Funding: Supported by the project "Improving anticancer immunotherapy efficacy of CAR-T cells or PD-1/PD-L1 inhibitors by combining immune modulators", funded by the Ministry of Education, Science, and Technological Development of the Republic of Serbia in the framework of scientific cooperation with the People's Republic of China (grant 451-03-1203/2021-09).
Competing interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Note for readers: several cited safety and toxicity analyses reference the authors' own prior in silico work from the same research group, which is disclosed in the paper text.

Study snapshot

Design	Narrative review of in vitro and in vivo (rodent and zebrafish) pharmacological and toxicological evidence.
Model	Review scope: cell culture models across pancreatic, breast, lymphoma, liver, leukaemia, prostate, colon, endometrial, and lung cancers; rodent and zebrafish models for the same cancer indications plus type 2 diabetes, obesity, cardiovascular disease (ischaemia, thromboembolism, hypertrophy), neurodegeneration (Alzheimer's, Parkinson's, multiple sclerosis, depression); protection against cadmium, chromium, arsenic, aluminium, and bisphenol A toxicity.
Sample	Not applicable (review of multiple primary studies; individual cited studies range from small in vitro experiments to animal cohorts of tens per group).
Intervention	Sulphoraphane doses reviewed span 0.1–100 μmol/L in vitro; 0.125–100 mg/kg (typically i.p.) in rodents; 3–50 μmol equivalent in zebrafish.
Duration	In vitro exposures from hours to days; in vivo studies from single dose to 4 months of dosing.
Endpoints	Nrf2-Keap1-ARE activation and phase II enzyme induction; tumour growth, apoptosis, and metastasis markers; insulin resistance, glucose tolerance, and diabetic complications (retinopathy, nephropathy, cardiomyopathy); adipocyte differentiation, browning of white adipose tissue, and body weight; cardiac function, platelet aggregation, and ischaemia-reperfusion injury; behavioural and pathological outcomes in neurodegeneration models; markers of oxidative damage and cytoprotection against toxic metals and bisphenol A

What the study showed, in plain terms

This is a broad narrative review from a University of Belgrade toxicology group, cataloguing what preclinical pharmacology and toxicology studies show about sulphoraphane across five major disease areas: cancer, diabetes and obesity, cardiovascular disease, neurodegeneration, and protection against environmental toxicants. It is deliberately wider in scope than a single-disease review and useful as a general reference for the compound rather than as a definitive verdict on any one indication.

The central mechanism the authors emphasise is activation of the transcription factor Nrf2. Sulphoraphane modifies cysteine residues on Keap1, the negative regulator of Nrf2, freeing Nrf2 to enter the nucleus and turn on genes for antioxidant defence and phase II detoxification enzymes. This one mechanism underlies most of the beneficial effects claimed across the disease areas: it suppresses inflammatory signalling via NF-κB, restores redox balance, and, at higher doses, tips cancer cells specifically into cell cycle arrest and apoptosis.

Across cancer models, sulphoraphane reduces tumour growth in mice with breast, colon, oesophageal, pancreatic, lung, and endometrial tumours, often with synergy when combined with standard chemotherapy. In diabetes models it improves glucose tolerance and prevents diabetic retinopathy, nephropathy, and cardiomyopathy. In obesity models it reduces fat accumulation and promotes browning of white adipose tissue. In cardiovascular models it protects against ischaemic damage and inhibits platelet aggregation. In neurodegeneration models it reduces amyloid-β burden and tau hyperphosphorylation in Alzheimer's mice, preserves dopaminergic neurons in Parkinson's models, and reduces demyelination in multiple sclerosis models.

The paper also assembles what is known about sulphoraphane's own toxicity. The authors' own in silico work suggests potential for hepatotoxicity, dermal effects, and mutagenicity at high exposures, and a mouse LD50 of about 213 mg/kg has been reported. In one lung cancer study, sulphoraphane given after tumour induction slightly increased tumour growth — a reminder that timing matters and that Nrf2 activation is not universally beneficial. The authors close by supporting dietary intake of cruciferous vegetables as safe and beneficial while calling for more toxicological work before higher-dose supplementation is recommended for chronic use.

Key findings

Nrf2-Keap1-ARE activation is the shared mechanism behind sulphoraphane's effects in cancer, diabetes, obesity, cardiovascular disease, and neurodegeneration. Downstream cytoprotective genes induced include NAD(P)H quinone oxidoreductase-1, heme oxygenase-1, catalase, glutamate-cysteine ligase, glutathione-S-transferase, UDP-glucuronosyltransferase, and superoxide dismutase.
Anticancer effects in animal models span breast (Castro 2019, Tsubura 2011), colon (Byun 2016), oesophageal (Lu 2021), pancreatic (Chen 2018), endometrial (Rai 2020), and lung (Chen 2019) tumours, at doses of 5–50 mg/kg intraperitoneally. Effects include inhibition of cell cycle, induction of apoptosis, and reduction in metastasis. Combination with paclitaxel or cisplatin shows synergy in several models.
Antidiabetic effects are mediated via the PI3K/Akt, JNK/IKK, and AMPK/mTOR pathways for insulin resistance; IRS-1/Akt/GLUT4 and PPAR/GLUT4 for glucose transport; and PPAR/GSK/GS for blood glucose control. Axelsson 2017 showed sulphoraphane reduces hepatic glucose production comparably to metformin via a different mechanism in mice, rats, and confirmatory human data.
Cardiovascular effects include cardioprotection from ischaemia-reperfusion injury via CaMKIIN2/CaMKIIδ modulation (Zhang 2022), inhibition of platelet aggregation via adenylate cyclase activation (Jayakumar 2013), and prevention of doxorubicin-induced cardiac fibrosis and hypertrophy via Nrf2 (Bai 2017).
Anti-obesity effects include reduced adipocyte size and lipid accumulation, activation of AMPK-mTOR-ULK1 lipophagy signalling, and browning of white adipose tissue via reversal of leptin resistance.
Neuroprotective effects in animal models include reduced amyloid-β burden and tau hyperphosphorylation in Alzheimer's mice, preservation of dopaminergic neurons and reduced motor deficits in Parkinson's models via 6-OHDA and MPTP, and reduced demyelination in experimental autoimmune encephalomyelitis models of multiple sclerosis. Most effects require Nrf2 (loss of protection in Nrf2 knockout mice).
Sulphoraphane also protects against cadmium, chromium, arsenic, aluminium, and bisphenol A toxicity in vitro and in animal models, largely by activating the same Nrf2-driven antioxidant response and inhibiting inflammatory cytokine production.
Safety signals to note: the mouse LD50 is approximately 213 mg/kg with TD50 around 192 mg/kg (Socala 2017); at very high doses (200 mg/kg), sulphoraphane lowered seizure thresholds in mice. In silico work by the authors' own group flags potential for chromosomal damage, skin effects, hepatotoxicity, mutagenicity, and eye/respiratory irritation. In one lung cancer model (Tao 2018), sulphoraphane given after tumour induction increased tumour numbers and size in both chemical and genetic mouse models.

What this study can and cannot tell us

This is a narrative review, not a systematic review or meta-analysis. There is no pre-registered search strategy, no formal risk-of-bias assessment, and no quantitative synthesis. The scope is deliberately broad, which is a strength for orientation and a limitation for depth on any one indication.

Almost all the pharmacological evidence catalogued is preclinical — cell culture, rodent, and zebrafish. Human clinical trial evidence is not the focus of this paper; readers looking for a clinical evidence synthesis in a specific area (e.g. autism, schizophrenia, cognitive ageing) will need condition-specific reviews.

Several of the toxicity claims rest on in silico analyses conducted by the authors' own research group and cited from their earlier papers. This is disclosed in the text but concentrates the safety argument in a single lab's computational predictions rather than in independent experimental toxicology. The authors explicitly call for more in vitro and in vivo work to validate these predicted adverse effects.

The interpretive framing across the paper is largely positive on sulphoraphane's therapeutic potential, with less attention to failed or null studies than a systematic review would give. Individual disease sections may therefore overstate the confidence in mechanisms that are still contested in the primary literature.

Dose-response and hormesis — the biphasic effects of sulphoraphane, where low doses protect and higher doses harm — are mentioned but not analysed in the depth other reviews (e.g. Calabrese and Kozumbo 2021) provide. This matters for any translation to human supplementation, where the therapeutic window is narrow.