Phlorotannins, a unique group of polyphenolic compounds derived exclusively from brown macroalgae (Phaeophyceae), have gained substantial scientific and industrial interest due to their structural diversity and multifaceted bioactivities. These marine metabolites, composed of phloroglucinol units linked through various C-C and C-O-C bonds, exhibit broad-spectrum antioxidant, anti-inflammatory, antimicrobial, antidiabetic, anticancer, and neuroprotective effects. Despite their promising in vitro efficacy, large-scale application remains hindered by three critical translational barriers: (i) extreme natural variability in phlorotannin content driven by ecological and seasonal factors, complicating raw material standardization; (ii) physicochemical instability and poor aqueous solubility resulting in limited oral bioavailability; and (iii) insufficient development of advanced delivery systems to ensure controlled release and targeted bioactivity. This comprehensive review integrates ecological, biochemical, and technological perspectives to establish a unified framework for translating phlorotannin research toward clinical and commercial realization. It systematically examines biosynthetic regulation, structural classification, extraction and purification methods, bioactivity mechanisms, pharmacokinetic barriers, and toxicological safety considerations. The review concludes by highlighting future research priorities essential for achieving industrial scalability, formulation reproducibility, and regulatory acceptance in marine bioactive development. Three interconnected challenges remain to successfully proceed with the implementation: The bioavailability problem, wherein phlorotannins exhibit poor oral bioavailability due to limited solubility, chemical instability, and extensive first-pass metabolism [ 6 , 20 , 21 ]; Raw material standardization issues, with natural variability of 0.5–30% of dry weight complicating industrial quality control [ 11 , 19 ]; The delivery system bottleneck, where advanced formulation strategies remain at proof-of-concept stages [ 6 , 21 ]. As illustrated in Figure 1 , biosynthesis proceeds through PKS1-catalyzed condensation of malonyl-CoA units, followed by tautomerization to yield phloroglucinol monomers, which undergo oxidative polymerization to generate diverse oligomeric structures [ 23 , 24 , 25 ]. Figure 1 Proposed biosynthetic pathway of phlorotannins in brown algae, showing the involvement of the acetate–malonate pathway and the role of type III polyketide synthase enzymes (PKS1) [ 24 , 25 ]. 2.2. Structural Diversity and Classification Phlorotannins are dehydro-polymers of phloroglucinol (1,3,5-trihydroxybenzene) [ 4 ]. Figure 2 Representative chemical structures of main phlorotannin classes: ( a ) phloroglucinol, ( b ) fucol, ( c ) diphloroethol, ( d ) tetrafucol-A, ( e ) phlorofucofuroeckol-B, ( f ) eckol, ( g ) dieckol, ( h ) 6,6′-bieckol, ( i ) fuhalol, and ( j ) carmalol [ 23 , 24 , 25 , 26 ]. Red lines depict oxygen bridges; blue lines depict carbon direct linkages. Biological activity depends on polymerisation degree and molecular weight [ 1 , 19 ]. Lower-molecular-weight oligomers exhibit better membrane permeability and cellular uptake, whereas higher-molecular-weight polymers demonstrate superior radical-scavenging properties due to the increased number of hydroxyl groups [ 1 ]. Phlorotannin Type Algal Source Extraction Method Biological Activities/Applications Remarks References Fucols Fucus vesiculosus Aqueous ethanol, solid–liquid Prebiotic effect, UV-radiation protection C–C linked phloroglucinol units; abundant in temperate brown algae [ 2 ] Phlorethols Ascophyllum nodosum Ethanol–water + ultrasound Antioxidant, neuroprotective Ether linkages; higher solubility than fucols [ 3 ] Fucophlorethol Sargassum muticum Deep eutectic solvent (DES) + ultrasound Antioxidant, enzyme inhibition Complex mixture; mixed linkages [ 36 ] Eckol Ecklonia cava (Lessoniaceae/Phaeophyta) Methanol extraction; SPE purification Antidiabetic, UV-protection, neuroprotective Dibenzo-1,4-dioxin ring [ 1 ] Dieckol Ecklonia cava / E. Phlorotannin therapeutic effectiveness is determined not by inherent biological potency—demonstrated across antioxidant, anti-inflammatory, antidiabetic, anticancer, and neuroprotective mechanisms—but by successful delivery to target tissues at therapeutically relevant concentrations [ 1 , 22 ]. The primary constraint is exceptionally low bioavailability from synergistic physicochemical and metabolic hurdles [ 1 , 22 ]. Phlorotannins exhibit limited aqueous solubility and poor membrane permeability, restricting passive diffusion across gastrointestinal epithelial barriers [ 22 ]. They demonstrate extreme chemical lability, being susceptible to degradation during storage, manufacturing, and gastrointestinal transit due to exposure to light, oxidative conditions, elevated temperatures, and pH extremes [ 1 , 22 ]. Surviving molecules undergo extensive biotransformation by gut microbiota, which enzymatically cleave oligomeric structures, frequently rendering compounds pharmacologically inactive [ 22 ]. This necessitates strategic reorientation from bioactivity screening toward development of advanced delivery systems [ 6 , 22 ]. (2021) elucidated how specific microbial metabolites—rather than intact parent structures—frequently serve as primary pharmacologically active entities [ 43 ]. Phlorotannin bioavailability is substantially influenced by binding interactions with dietary macromolecules and food matrix components [ 22 ]. Phlorotannins exhibit strong affinity for proteins, carbohydrates, and lipids through hydrogen bonding, hydrophobic interactions, and electrostatic associations, forming insoluble complexes that reduce bioaccessibility [ 22 ]. Arazo-Rusindo et al. (2025) demonstrated that matrix composition profoundly influences phlorotannin release, stability, and absorption potential [ 20 ].