Pomegranate (Punica granatum L.) has long been recognised for its rich antioxidant profile and potential health benefits. Recent research has expanded its therapeutic potential to include antiangiogenic properties, which are crucial for inhibiting the growth of tumours and other pathological conditions involving aberrant blood vessel formation. This review consolidates current findings on the antiangiogenic effects of pomegranate extracts. We explore the impact of pomegranate polyphenols, including ellagic acid, punicalagin, anthocyanins, punicic acid and bioactive polysaccharides on key angiogenesis-related pathways and endothelial cell function. Emphasis is placed on the effects of these extracts as phytocomplexes rather than isolated compounds. Additionally, we discuss the use of pomegranate by-products, such as peels and seeds, in the preparation of extracts within a green chemistry and circular economy framework, highlighting their value in enhancing extract efficacy and sustainability. By primarily reviewing in vitro and in vivo preclinical studies, we assess how these extracts modulate angiogenesis across various disease models and explore their potential as adjunctive therapies for cancer and other angiogenesis-driven disorders. This review also identifies existing knowledge gaps and proposes future research directions to fully elucidate the clinical utility of pomegranate extracts in therapeutic applications.

Pomegranate marc is a major, underutilized juice industry by-product rich in lipophilic polyunsaturated fatty acids—notably conjugated α-linolenic acids (CLnAs)—and hydrophilic polyphenols with potent antioxidant and anti-inflammatory properties. Despite its potential for nutraceutical, cosmetic, and pharmaceutical applications, this matrix remains largely unexploited. This study presents a novel, sequential in-line extraction strategy combining supercritical CO₂ (ScCO₂) and subcritical water (scW) to recover complementary bioactive fractions. Both extraction steps were optimized via Response Surface Methodology (RSM). Box–Behnken optimization of ScCO₂ (43 MPa, 76 °C, 6.4 L min⁻¹, 124 min) yielded 30 g kg⁻¹ dry weight (dw) of oleoresin, achieving a 68% recovery of total oil. Subsequent scW extraction was optimized at 149 °C, with a 40 L kg⁻¹ water-to-solute ratio and 73 min extraction time, yielding 47 g kg⁻¹ dw of total phenolics (58% recovery). Strong agreement between experimental and predicted values confirmed the robustness of the models. Comprehensive profiling revealed a diverse phytocomplex including fatty acids, tocopherols, flavonoids, soluble sugars, and polysaccharides. Antioxidant assays confirmed that both γ-tocopherol and polyphenols significantly contribute to the extracts’ bioactivity. To improve physical handling, the aqueous fractions were converted into solid dispersions via spray drying with maltodextrin. Preliminary in vitro biological assessments on HEK-293 (human embryonic kidney) and MCF-7 (Michigan Cancer Foundation-7) cell lines suggested that the maltodextrin-based formulations may modulate the cytotoxic profile compared to the free extract, with exploratory results showing dosage-dependent variations in cell viability across the two lines. This work suggests a potentially scalable and sustainable biorefinery approach for the integral valorisation of pomegranate marc, offering a basis for a pathway to produce solvent-free bioactives.