3.1. Traditional Uses

Given that traditional medical practices often rely on local flora, fauna, and mineral resources, V. vinifera has been utilized by various cultures since antiquity for its therapeutic properties [Table 1] [25,26]. Ethnomedicinal data indicate that fruits have been employed for a range of health conditions, including immune system stimulation and cough suppression, often administered in the form of molasses or syrup to treat diphtheria. Alcoholic macerates of the fruit have been traditionally used for the management of rheumatism, while grape vinegar has been applied in the treatment of common colds. The juice is frequently consumed to relieve abdominal pain and toothaches, which may also be addressed using fruit decoctions. In addition, the consumption of fresh grapes has been associated with the alleviation of nasopharyngitis symptoms [25-29].

Historical sources also document the use of grapes for hepatic function maintenance [30] and describe both unripe grape juice and dried fruits as effective antitussive agents. Dried grapes are traditionally recognized for their expectorant properties, benefits to the trachea, and nutritional value. Moreover, grape juice has been used in folk medicine as a preventive measure against syncope [31], while fruit mash and syrup are reputed to strengthen general vitality, including the support of hematologic and thyroid functions [32].

Other plant parts have also been employed therapeutically: the root has been used to manage hypertension [25], and the leaves – either in decoctions or aqueous macerates – have been applied for treating sunburn, ocular inflammation, and urinary disorders [33,34]. Furthermore, Ayurvedic medicine includes V. vinifera in polyherbal formulations for the treatment of epilepsy and for managing conditions affecting the liver, spleen, respiratory system, and gastrointestinal tract, including complications arising from chemotherapy [35,36].

3.2. Chemical Composition

The fruit of V. vinifera is notably rich in flavonoids [37], with anthocyanins playing a pivotal role in pigmentation and exhibiting therapeutic potential, particularly in the management of type 2 diabetes mellitus (T2DM), due to their potent antioxidant properties [38]. In addition, anthocyanins have demonstrated neuroprotective effects by ameliorating memory impairment and protecting neural tissue against oxidative stress [39]. Quantitative analysis of the roots of V. vinifera revealed total phenolic and flavonoid contents of 2.85 ± 1.10 mg gallic acid equivalents per gram and 2.51 ± 1.27 mg quercetin equivalents per gram of dry weight, respectively [40,41]. Furthermore, ultra-performance liquid chromatography coupled with tandem mass spectrometry enabled the identification of several key phenolic and flavonoid constituents in the fruits, including trans-4-hydroxycinnamic acid methyl ester, pelargonidin 3-O-glucoside, quercetin-3-O-glucoside, and cyanidin 3-O-glucoside, all of which contribute to the plant’s antioxidant capacity [40,42]. Among these, quercetin-3-O-glucoside has demonstrated inhibitory activity against glutamine synthetase and possesses antimycobacterial properties, indicating its potential as a lead compound for anti-tuberculosis drug development [43]. Cyanidin 3-O-glucoside has shown promise in the prevention and treatment of neurological disorders such as cerebral ischemia, Alzheimer’s disease, and Parkinson’s disease [44,45], in addition to exerting protective effects on intestinal health [46] and displaying therapeutic potential in non-alcoholic fatty liver disease [47]. A comprehensive summary of these bioactive compounds and their pharmacological attributes is presented in Table 2.

V. vinifera seeds [Table 3] are characterized by a high lipid content, with linoleic acid comprising over 50% of the total fatty acids [5,48-50]. Linoleic acid, an essential omega-6 polyunsaturated fatty acid, plays a crucial role in human metabolism due to the inability of endogenous synthesis [50]. Other significant fatty acids identified in the seeds include oleic, palmitic, and stearic acids [5,50]. In addition to lipids, V. vinifera seeds contain substantial quantities of polyphenols, flavonoids, phenolic acids, organic acids, and catechin oligomers, all of which contribute to their antioxidant potential [5,50,51]. Owing to this composition, grape seeds are considered promising candidates for health-beneficial oil production [5].

The skins of V. vinifera also represent a rich source of polyphenolic compounds, particularly flavan-3-ols [Table 4]. Four monomeric flavan-3-ols – (+)-catechin, (−)-epicatechin, epigallocatechin gallate, and epicatechin gallate – along with 10 oligomeric forms (comprising three dimers, four trimers, two tetramers, and one pentamer) have been identified [52,53]. Epidemiological evidence strongly correlates increased intake of flavan-3-ols with a decreased risk of cardiometabolic diseases [54]. In addition, (+)-catechin and (−)-epicatechin exhibit significant α-glucosidase inhibitory activity, highlighting their utility in glycemic control [55]. Flavonols such as catechin, epicatechin, quercetin-3-O-glucoside, myricetin, and isorhamnetin-3-O-hexose, alongside stilbenoids such as resveratrol-3-O-glucoside, serve as key biochemical markers of grape ripening [8,13]. These compounds not only inform optimal harvest periods but also play essential roles in the antioxidant properties of grape skins. Furthermore, anthocyanins, hydroxybenzoic acids, hydroxycinnamic acids, and various organic acids contribute to the strong antioxidant activity of grape skins, primarily due to the extensive diversity of polyphenols [8,13,56]. This chemical profile holds relevance to the enological sector, where such metabolites significantly influence fermentation dynamics and final product quality [49].

In addition to polyphenolic compounds, the fruit of V. vinifera contains triterpenic acids with significant pharmacological potential, particularly oleanolic acid. This compound exhibits a broad spectrum of bioactivities, including antidiabetic, antitumor, anti-inflammatory, antibiotic, and antiviral effects. Notably elevated levels of oleanolic acid have been identified in specific grape cultivars, such as Aglianico [57]. Regarding the terpenoid profile, substantial enantiomeric excesses in volatile compounds have been observed in Moscato Giallo grapes and wines, suggesting biosynthetic pathway specificity within V. vinifera. These findings represent the first reported investigation into the chiral characteristics of grape-derived terpenoids [58].

The stems (or stalks) of V. vinifera [Table 5] are particularly rich in phenolic compounds, with gallic acid emerging as the most abundant [9,59]. Gallic acid has demonstrated therapeutic potential for a variety of oxidative stress-related diseases, including cancer, cardiovascular and neurodegenerative disorders, and metabolic syndromes. Its anti-inflammatory properties are mediated primarily through modulation of the mitogen-activated protein kinases and nuclear factor-κB (NF-κB) signaling pathways, resulting in reduced expression of pro-inflammatory cytokines, chemokines, adhesion molecules, and immune cell infiltration [60,61]. Additional phenolic compounds identified in grape stems include caftaric acid, malvidin-3-O-glucoside, quercetin-3-O-glucuronide, malvidin-3-O-(6-O-caffeoyl)-glucoside, and Σ-viniferin [62]. The flavonoid profile includes (+)-catechin, procyanidin, procyanidin B2, (−)-epicatechin, (−)-epigallocatechin gallate, (−)-epicatechin gallate, naringin, quercetin-3-galactoside, quercetin-3-glucoside, myricetin, astilbin, and apigenin. Hydroxycinnamic acid derivatives such as syringic and caftaric acids, along with hydroxytyrosol, further contribute to the antioxidant capacity of grape stems [3,63]. In addition, stems are a source of essential minerals, including potassium, calcium, magnesium, and sodium [6]. These attributes support the potential repurposing of grape stems as sustainable and economically viable sources of bioactive compounds for pharmaceutical, nutraceutical, and functional food applications [3,9].

The leaves of V. vinifera [Table 6] also present a rich phytochemical profile, containing substantial quantities of tannins, flavonoids, and total phenolic compounds [14]. Identified constituents include caffeic acid, catechin, kaempferol, quercetin, rutin, ellagic acid, and phytosterols [64,65]. The high antioxidant activity of grape leaves is attributed to these compounds [64]. Fatty acid profiling revealed alpha-linolenic acid as the predominant species (42%), followed by linoleic (25%) and palmitic (22%) acids. Leaves also contain relevant mineral elements such as calcium, sodium, boron, and potassium [65]. These findings underscore the utility of grape leaves as an affordable source of functional ingredients with applications in the food and pharmaceutical industries [14,64,65].

Despite the broad chemical characterization of grape tissues, it is well-established that both environmental and anthropogenic factors significantly influence the qualitative and quantitative expression of phytochemicals. For instance, reduced sun exposure leads to diminished phenolic content, whereas the use of silver reflective mulch enhances their accumulation [66]. Similarly, the application of plant hormones such as methyl jasmonate has been shown to elevate secondary metabolite production [67]. The developmental stage also plays a crucial role, as demonstrated in Suo Suo grapevines, where the maximal concentrations of cyanidin-3-O-glucoside, fructose, tartaric acid, and oleanolic acid were recorded between the 105^th and 135^th day of growth [68].

Moreover, the phenolic content varies between free and bound forms. In the Corinthian grape variety, bound phenolics were predominant, with p-hydroxybenzoic acid as the principal aglycone, while caftaric acid and miquelanin represented the main free phenolic compounds [69]. Moreover, genetic background and mutations further contribute to the phenolic diversity in grapes. An investigation encompassing 27 clones from eight cultivars across two growing seasons examined 24 polyphenolic compounds along with the physicochemical properties of the grapes and resultant wines. The study revealed significant inter- and intra-varietal variation. Orthogonal partial least squares discriminant analysis identified malvidin-3-O-glucoside, peonidin-3-O-glucoside, and epicatechin as key biomarkers for distinguishing grape and wine samples [70].

3.3. Pharmacological Activities

Table 7 presents a summary of the in vitro bioactivities of phytochemical constituents derived from V. vinifera. Among these, ellagic acid, gallotannins, and quercetin have demonstrated notable antibacterial activity, primarily through the inhibition of bacterial DNA gyrase, thereby disrupting DNA replication processes [51,71]. Gallic acid exerts its antimicrobial effects through the chelation of divalent metal cations and by promoting the permeabilization and structural disintegration of the outer membrane in Salmonella species [71].

Overall, V. vinifera phytochemicals display greater antibacterial efficacy against Gram-positive bacteria compared to Gram-negative species. This differential activity is attributed to the complex outer membrane of Gram-negative bacteria, which contains lipopolysaccharides (LPSs) that form a robust, hydrophilic barrier limiting the diffusion of antimicrobial agents. In contrast, the simpler peptidoglycan-rich membrane of Gram-positive bacteria permits easier penetration of lipophilic compounds. Furthermore, Gram-negative bacteria possess multiple efflux pump systems that actively expel antimicrobial molecules, thereby reducing their intracellular accumulation and effectiveness [71,72].

In addition to their bactericidal properties, polyphenol-rich grape extracts have been shown to significantly inhibit the adhesion of key pathogenic bacteria – including Salmonella enterica, Klebsiella pneumoniae, Staphylococcus aureus, and Escherichia coli – to human epithelial cell lines (Caco-2 and HaCaT), while preserving host cell integrity. These extracts selectively impede the adhesion of pathogenic species while promoting colonization by commensal microorganisms, thereby contributing to microbial homeostasis at mucosal surfaces. Furthermore, the extracts mitigate oxidative stress, reinforce epithelial barrier function, and downregulate pro-inflammatory cytokines such as IL-6 and IL-8 in LPS-stimulated cells. These cytoprotective effects are mediated predominantly through the activation of the Nrf2 signaling pathway [73].

Further evidence of the antimicrobial potential of grape by-products was provided by a study examining the effects of grape residue extracts on Staphylococcus epidermidis ATCC 35984 and Pseudomonas aeruginosa PA14. Hydromethanolic grape pomace extract – obtained through ultrasound-assisted extraction with 80% methanol – exhibited the highest antibiofilm efficacy, inhibiting biofilm formation by 99% in S. epidermidis and 80% in P. aeruginosa. This extract also disrupted existing Gram-negative bacterial biofilms, enhanced swarming motility, and induced marked morphological alterations in bacterial cells. Toxicological evaluation using the Caenorhabditis elegans model demonstrated the extract’s safety profile, with no observed acute or chronic toxicity, underscoring its potential as a safe and effective antimicrobial agent [74].

The antioxidant capacity of V. vinifera has been extensively evaluated using established in vitro assays. These include the ABTS°+ radical cation decolorization assay and the DPPH free radical scavenging method, both of which demonstrated a strong positive correlation between antioxidant activity and the total phenolic, flavonoid, and tannin content of the fruit [11,18,62]. Oleic acid, a key fatty acid present in V. vinifera, has also been reported to exhibit significant free radical scavenging activity, contributing to its antioxidant potential [75]. In addition, the unsaponifiable fraction of V. vinifera seed oil has demonstrated both antioxidant and anti-inflammatory properties. This bioactivity is mediated through the modulation of monocyte plasticity, favoring the anti-inflammatory CD14+ CD16++ phenotype and suppressing pro-inflammatory responses by downregulating the expression and secretion of tumor necrosis factor-alpha, interleukin (IL)-1β, and IL-6 in human primary monocytes [76].

In vivo investigations [Table 8] corroborate the antioxidant potential of V. vinifera, demonstrating reductions in lipid peroxidation within muscle tissue [15] and improvements in oxidative stress markers, including cardiac parameters [77]. Although the specific bioactive molecules responsible for these effects remain unidentified, the antioxidant activity of the extracts is directly proportional to their polyphenolic concentration [15,77]. Further in vitro assays performed on seed extracts from Muscat and Quebranta grape varieties demonstrated significant antioxidant capacity, as evidenced by DPPH radical scavenging (IC₅₀ values of 38.60 ± 0.624 μg/mL and 42.83 ± 0.306 μg/mL, respectively) and ferric reducing antioxidant power assays (0.79 ± 0.030 μg Trolox equivalent [TE]/g and 0.61 ± 0.038 μg TE/g, respectively). Notably, these extracts also exhibited hypoglycemic activity in an alloxan-induced hyperglycemia model in Rattus norvegicus, with oral administration of 500 mg/kg of biophenol and polyunsaturated fatty acid-rich extracts, significantly reducing blood glucose levels [78].

The antiviral activity of V. vinifera phytochemicals has also been documented. Vitisin B, a pyranoanthocyanin compound, was shown to inhibit neuraminidase activity and suppress H1N1 influenza virus replication in MDCK and A549 cell lines. Mechanistically, vitisin B mitigates virus-induced ROS generation by upregulating glucose-6-phosphate dehydrogenase expression and Nrf2 pathway activation while concurrently inhibiting NF-κB nuclear translocation through IκB kinase dephosphorylation. In in vivo models, vitisin B attenuated body weight loss, reduced viral titers, and diminished lung inflammation, thereby enhancing survival in influenza A-infected mice [79].

The anticancer potential of V. vinifera has been validated through both in vitro and in vivo models. In vitro analyses [Table 7] indicate that extracts from various plant parts can induce apoptosis through intrinsic (mitochondria-dependent) and extrinsic (death receptor-mediated) pathways. Central to the intrinsic pathway is the Bax/Bcl-2 ratio, with increased Bax expression and decreased Bcl-2 levels promoting apoptotic progression. Ethanolic leaf extracts reduced Bcl-2 expression and increased Bax levels in breast and hepatocarcinoma cell lines, likely due to polyphenolic constituents, particularly flavan-3-ols, with high antioxidant activity [80]. Similarly, methanolic grape extracts exhibited pro-apoptotic effects against human colon adenocarcinoma cells, with oleanolic acid identified as the principal active compound [75].

In in vivo models [Table 8], anticancer activity was demonstrated using gold nanoparticles synthesized from grape peel and seed extracts, which inhibited tumor cell proliferation during papilloma genesis. Although the specific active constituents were not identified, the chemopreventive effect was attributed to the antioxidant capacity of grape polyphenols [81]. Furthermore, the saponifiable fraction of black grape seed oil exhibited potent cytotoxic activity against Caco-2, PC-3, NFS-60, and especially HepG-2 cells, as well as in a p-dimethylaminoazobenzene-induced hepatocellular carcinoma (HCC) mouse model, outperforming the chemotherapeutic agent 5-fluorouracil (5-FU). The observed effects were associated with the phenolic, fatty acid, and vitamin content of the extract, which contributed to its antioxidant, apoptotic, anti-inflammatory, anti-metastatic, and anti-hypoxic properties. In addition, this fraction competitively inhibited several oncogenic targets, including NBD-NOX2, HDAC1-MTA1, and SepR [82].

Moreover, the saponifiable fractions from both black and green grapes demonstrated superior cytotoxic activity against MCF-7 breast cancer cells and Ehrlich ascites carcinoma cells compared to 5-FU. These effects were associated with the induction of oxidative stress in cancer cells and were independent of AMP-activated protein kinase signaling. In addition, these extracts inhibited cancer cell migration through the downregulation of CD44+ cells and proposed competitive inhibition of matrix metalloproteinase-9 and cathepsin B activities [83].

Further in vitro studies with polyphenolic fractions from V. vinifera (VVF1, VVF2, and VVF3) revealed significant anticancer activity against HepG2 and Huh7 HCC cell lines, with efficacy surpassing that of 5-FU. These fractions displayed cytotoxicity within safe therapeutic margins and effectively eliminated CD133+ cancer stem cell (CSC) populations, indicating a potential anti-CSC mechanism. In a p-DAB-induced HCC mouse model, VVF1 and VVF2 targeted key hallmarks of CSC-mediated tumor progression – including sustained proliferation, therapeutic resistance, angiogenesis, invasion, and metastasis – through the modulation of apoptosis, inflammation, drug resistance, hypoxia, epithelial-mesenchymal transition, and extracellular matrix degradation pathways. Among the three, VVF1 exhibited the most potent anticancer effects. These outcomes were attributed to synergistic interactions among phenolic constituents, which also exerted inhibitory activity against oncogenic enzymes such as NADPH-NOX2, HDAC1-MTA1, and SepR, validating their potential as therapeutic targets in HCC [84].

Recent studies have identified novel bioactivities associated with V. vinifera by-products. For the first time, anti-tyrosinase activity was reported in wet pomace extracts [Table 7] [11]. Similarly, the hydroethanolic extract of grape stems exhibited an anti-aging effect through the inhibition of both tyrosinase and elastase enzymes [Table 8] [59]. Although the specific compounds responsible for these effects have yet to be fully characterized, known tyrosinase inhibitors such as quercetin and gallic acid are likely contributors [11]. In addition, the antiproliferative efficacy of grape extracts was significantly enhanced through nanoencapsulation techniques. Notably, nanoencapsulated grape extracts (NEGEs) derived from Marselan and Obeidi varieties markedly suppressed the proliferation of B16–F10 melanoma cells, with the Obeidi-derived NEGEs exhibiting the strongest activity [85].

The nephroprotective properties of V. vinifera have also been substantiated in experimental models. Co-administration of 2% grape seed extract (GSE) and selenium (1:1 ratio) significantly mitigated ochratoxin A (OTA)-induced renal damage in rats. This combination reduced lipid peroxidation and improved enzymatic and non-enzymatic antioxidant defenses. The most robust protective effect was observed with the GSE 2% + selenium combination, followed by GSE 2% alone and selenium alone (0.4 mg/kg). Histopathological analyses supported these findings, revealing severe renal tubular degeneration in OTA-treated rats, while those treated with GSE and grape peel extract displayed only mild renal alterations. The GSE 2% + selenium group exhibited nearly normal kidney histology, underscoring the combination’s superior protective efficacy [86].

Grape-derived compounds have also shown promise in managing metabolic disorders. Grape seed proanthocyanidin extract (GSPE) demonstrated a protective role in T2DM by inhibiting ferroptosis in pancreatic β-cells. GSPE treatment enhanced the expression of glutathione peroxidase 4 and cystine/glutamate antiporter, key regulators of ferroptosis. Both in vitro and in vivo studies confirmed that GSPE attenuated ferroptosis and improved β-cell viability through activation of the Nrf2 signaling pathway [87].

In the context of nociception, dietary supplementation with GSE preserved normal levels of γ-aminobutyric acid (GABA)-synthesizing enzymes and Gi-coupled GABA B receptors in a rat model of temporomandibular disorder (TMD). This preservation effectively prevented the development of prolonged nociceptive responses following sustained jaw opening. These findings suggest that GSE supplementation may reduce the risk of chronic TMD in susceptible individuals [88].

The neuroprotective and cognitive benefits of V. vinifera have also been investigated. Proanthocyanidin extracts administered intraperitoneally in mice demonstrated anxiolytic, anticonvulsant, and sedative effects and ameliorated memory deficits following status epilepticus [Table 8] [89]. While the precise mechanisms remain unclear, these effects may be mediated through enhanced synaptic transmission in the hippocampus and inhibition of beta-amyloid oligomer aggregation [89,90]. In addition, vitisin A, a resveratrol tetramer, exhibited neuroprotective properties when centrally administered, promoting synaptic plasticity and neuronal viability while restoring memory and cognitive function in scopolamine-treated mice. These effects are partially attributed to the upregulation of brain-derived neurotrophic factor, cAMP response element-binding protein, and calcium/calmodulin-dependent protein kinase II signaling pathways [91]. Another resveratrol derivative, α-viniferin, a trimer, significantly inhibited monoamine oxidase, thereby elevating striatal dopamine levels and enhancing behavioral performance in mice, suggesting its potential for neurodegenerative disease therapy [92].

Ophthalmological benefits have also been observed. A diet enriched with grape powder (GP) effectively suppressed ultraviolet (UV)-induced cataractogenesis in a dose-dependent manner and maintained intraocular glutathione levels. Notably, GP-fed groups did not exhibit UV-induced Nrf2 activation, implying that GP promotes redox homeostasis independently of this pathway. Proteomic analysis identified 471 proteins modulated by GP intake, with the X-linked inhibitor of apoptosis protein (XIAP) emerging as a key molecular target. Bioactive compounds such as resveratrol, catechin, quercetin, and anthocyanins were found to interact with XIAP. Experimental validation confirmed that GP prevented UV-induced XIAP suppression, thereby implicating XIAP in the molecular mechanism underlying GP’s protective effect against cataract formation [93].

Recent clinical studies have provided evidence supporting the therapeutic efficacy of V. vinifera-derived products in the management of various pathological conditions and symptomatic relief. Notably, Cognigrape^®, a dietary supplement formulated from grape extract, demonstrated significant cognitive benefits in healthy older adults. Participants receiving Cognigrape^® showed marked improvements in Mini-Mental State Examination scores relative to both baseline and placebo controls. Furthermore, reductions of 15.8% and 24.9% were observed in the Beck Depression Inventory and Hamilton Anxiety Rating Scale scores, respectively. The Repeatable Battery for the Assessment of Neuropsychological Status total score also significantly increased following supplementation. Compared to the placebo group, Cognigrape^® administration was associated with improved performance in attention, language, and both immediate and delayed memory domains, while visuospatial/constructional abilities remained unchanged. No adverse events were reported during the intervention, indicating a favorable safety profile [94].

In vascular health, a randomized non-inferiority clinical trial evaluated the effects of V. vinifera seed extract compared to micronized purified flavonoid fraction (MPFF) in patients with chronic venous disease. A total of 303 participants were randomly assigned to receive either V. vinifera seed extract (n = 154) or MPFF (n = 149) over 8 weeks. Both groups exhibited statistically significant improvements in Chronic Venous Insufficiency Questionnaire 20 scores from baseline, with no significant difference between the two treatments. The lower bound of the confidence interval for the difference in mean score reduction remained within the predefined non-inferiority margin of 6.9, confirming the non-inferiority of the GSE. Additional clinical outcomes, including scores on the Aberdeen Varicose Vein Questionnaire, Visual Analog Scale, and Venous Clinical Severity Score, improved significantly in both groups at weeks 4 and 8. Importantly, patients receiving V. vinifera seed extract exhibited a significant reduction in calf circumference by week 8, further supporting its efficacy [95].

In addition, the potential genoprotective effect of red grape juice was assessed in a controlled study involving 20 healthy adults (10 males and 10 females), randomized into a grape juice group and a control group receiving water. Participants in the treatment group consumed a single 250 mL dose of additive-free commercial red grape juice. Analysis revealed a statistically significant reduction in DNA damage among individuals who consumed grape juice compared to the control group. These findings suggest that even a single dose of red grape juice may confer short-term protection against oxidative stress-induced genotoxicity [96].

3.4. Techniques Used to Modify the Chemical Composition of V. vinifera

One of the principal consequences of global climate change is the acceleration of vegetative and reproductive phases in grapevines. Elevated temperatures pose a significant threat to grape berry development by inducing heat stress, which may compromise both the compositional integrity and the medicinal and commercial value of grapes. Climate-driven alterations extend beyond primary metabolites – such as organic acids (notably malic acid), sugars, and amino acids – to secondary metabolites, including flavonoids and aroma precursors. Multi-omics approaches (transcriptomic, proteomic, and metabolomic analyses) have elucidated these complex shifts in grape biochemical profiles under thermal stress conditions [97].

To mitigate the adverse impacts of climate change and enhance the accumulation of desirable compounds, various agronomic and enological strategies have been developed. These include hormonal treatments, soil amendment practices, the incorporation of bioactive compounds, and targeted interventions during both pre- and post-fermentation maceration stages. For instance, foliar application of monosilicic acid during grape ripening resulted in wines with reduced levels of acetic acid, acetaldehyde, ethyl acetate, and diacetyl while simultaneously increasing the concentrations of total phenolics, anthocyanins, and tannins – compounds typically diminished in wines derived from Botrytis cinerea-affected grapes [98].

Soil composition has also emerged as a critical determinant of phenolic compound accumulation. Soils with low water-holding capacity are associated with reduced foliar phenolic content, while environmental stressors such as cold exposure, water deficits, and temperature variability have been shown to decrease overall phenolic concentrations in grapevines [2]. Nonetheless, the exogenous application of kaolin before veraison significantly improved berry quality by enhancing berry size, secondary metabolite levels, and seed antioxidant activity, suggesting its potential as an adaptive strategy under climate stress conditions [99]. Furthermore, combining chitosan and gelatin with GSE augmented its antioxidant capacity by increasing total phenol content, improving elasticity, and inhibiting microbial proliferation [10].

Winemaking techniques also exert a substantial influence on the final phenolic profile and organoleptic properties of wine. Interventions such as maceration and exogenous tannin addition have been shown to modify phenolic composition, color characteristics, and the macro- and micro-elemental profile of wines [100,101]. Specifically, pre-fermentative heating in combination with maceration significantly enhanced antioxidant capacity, while extended post-fermentative maceration (21 days) elevated the levels of hydroxybenzoic acids, flavan-3-ols, and macro-elements [102]. Cold pre-fermentative maceration selectively increased phenolic content without exacerbating astringency or bitterness, whereas prolonged post-fermentative maceration was more influential in modulating color intensity and the broader phenolic spectrum, underscoring the importance of tailoring winemaking strategies to desired outcomes [103].

In addition, the implementation of silver reflective mulch has consistently improved grape maturity by enhancing the accumulation of total phenols, tannins, and anthocyanins in grape skins. This technique contributes to elevated phenolic content in the resulting wines and enhances color expression, thus representing another viable method for quality preservation in the face of climatic variability [66].