Neurological and neurodegenerative diseases such as multiple sclerosis (MS), ischemic stroke, and Alzheimer’s disease (AD) continue to represent major public health challenges, with limited therapeutic options capable of preventing or reversing neuronal and glial damage [1, 2]. Increasing evidence indicates that these disorders share convergent pathological mechanisms (including oxidative stress, chronic neuroinflammation, mitochondrial dysfunction, and impaired remyelination) that collectively drive disease progression [3, 4]. Targeting these interconnected processes is therefore a key strategy for developing multitarget therapies applicable across different central nervous system (CNS) conditions.

In this context, phycocyanobilin (PCB), the covalently bound prosthetic group of the cyanobacterial protein C-phycocyanin (CPC), emerges as a promising bioactive compound with antioxidant, anti-inflammatory, and neuroprotective properties. Experimental studies in both animal and cellular models have shown that PCB mitigates behavioral, histological, and molecular alterations associated with autoimmune and neurodegenerative damage [5]. Moreover, transcriptomic and histological evidence support its ability to promote oligodendrocyte survival and remyelination, thereby adding a regenerative dimension to its protective profile [6].

Recent advances in heterologous PCB biosynthesis, particularly in E. coli systems, enable the production of reproducible, high-purity, and scalable material suitable for mechanistic and translational research [7]. Such progress bridges natural pigment pharmacology with modern biotechnology, paving the way for clinical development.

This mini-review integrates current evidence on PCB’s neuroprotective actions, elucidates its molecular mechanisms, and highlights recent progress in its biotechnological production and translational prospects.

PCB serves as the covalently bound prosthetic group of phycobiliproteins (most prominently CPC) in cyanobacteria such as Spirulina platensis. Within CPC, PCB is attached via thioether linkages to conserved cysteine residues within the α/β subunits [8], as illustrated in Figure 1A.

Structurally related to biliverdin and bilirubin, PCB exhibits potent antioxidant and anti-inflammatory activities through the modulation of redox-sensitive signaling pathways and the preservation of mitochondrial homeostasis [9, 10]. The free PCB molecule, represented in Figure 1B, retains the conjugated tetrapyrrolic structure that confers these redox and radical-scavenging properties.

PCB can be obtained through two complementary and translationally relevant production routes: Natural extraction from cyanobacterial biomass (most commonly Spirulina) which yields PCB covalently bound as the prosthetic group of CPC [11, 12]; and heterologous biosynthesis, primarily in E. coli, which enables the production of free PCB as a recombinant linear tetrapyrrole molecule with enhanced purity, reproducibility, and scalability [13, 14].

These advances in biotechnological production are pivotal for translational development, providing consistent material for mechanistic and preclinical studies while overcoming the intrinsic limitations of natural biomass sources.

Taken together, the structural versatility and scalable production routes of PCB provide the basis for advancing its neuroprotective and remyelinating potential in experimental models.

The beneficial effects of PCB on the CNS are explained through several interrelated molecular mechanisms that converge on the control of oxidative stress and neuroinflammation (Figure 2) [6, 12, 17].

Natural extraction of PCB from cyanobacterial biomass traditionally involves isolating CPC holoproteins containing covalently bound PCB, followed by chromatographic enrichment and, when free PCB is required, controlled cleavage and bilin release [30, 31]. Although feasible, this route is limited by batch-to-batch variability in pigment content, isoforms, and purity, as well as by the presence of proteinaceous impurities and other bilins, which complicate downstream analytics [30].

Recent advances have shifted attention toward heterologous biosynthesis in E. coli, where the cyanobacterial heme-to-bilin pathway is reconstituted by co-expression of HO-1 and PCB: ferredoxin oxidoreductase (PcyA). Optimized ribosome binding sites, codon usage, and metabolic engineering strategies have enabled intracellular PCB accumulation at higher yields and purity [7, 32, 33]. Importantly, recombinant production provides a scalable source of free PCB, thereby overcoming the variability inherent to natural extracts.

For translational applications, two technical aspects are particularly critical and must be rigorously addressed to ensure safety and reproducibility. Endotoxin control is indispensable, as the removal of lipopolysaccharides derived from Gram-negative expression hosts is essential for parenteral administration; residual endotoxins can elicit strong immunogenic responses and compromise therapeutic applicability. Equally important is the assurance of analytical identity and purity, which requires comprehensive characterization through combined high-performance liquid chromatography (HPLC), ultraviolet-visible spectroscopy, and mass spectrometry criteria. This integrated approach confirms the correct bilin identity while excluding oxidized or degraded by-products, thereby safeguarding molecular integrity and functional consistency [7, 33].

In addition, PCB stability and formulation strategies remain an active area of research. Like other tetrapyrroles, PCB is both photo and redox-sensitive, requiring protective measures such as opaque containers, antioxidants, and controlled pH conditions [30]. Preclinical work has explored cyclodextrin complexes, liposomal carriers, polymeric nanoparticles, and intranasal delivery routes to enhance solubility, stability, and potential brain exposure. These approaches highlight the growing integration of biotechnological production with pharmaceutical formulation science [30, 31].

Despite promising preclinical data, several challenges must still be addressed before PCB can advance to clinical use. The first challenge relates to pharmacokinetics and BBB permeability, as direct evidence of PCB penetration into the CNS remains limited [6]. Clarifying whether PCB acts centrally or through peripheral immunometabolic modulation will require standardized biodistribution assays, including liquid chromatography-tandem mass spectrometry (LC-MS/MS), plasma-to-brain ratio measurements, and radiolabeled tracing. Furthermore, toxicological and clinical data on PCB represent a significant gap, given the lack of formal toxicological evaluation of the molecule. Although CPC and Spirulina are generally recognized as safe (GRAS) [34] for dietary use, intravenous or chronic administration of PCB will require rigorous safety studies and, ultimately, clinical trials.

From a regulatory standpoint, PCB may follow a nutraceutical pathway, leveraging its existing GRAS status but limiting therapeutic claims, or a drug development pathway, which requires comprehensive pharmaceutical evaluation [35] but allows for specific disease indications. Additionally, the potential for combinatorial use of the molecule should be considered. Given its multitarget profile, PCB may complement DMTs in MS [6] or be combined with antioxidants in AD and stroke [36], potentially enhancing neurorepair and remyelination.

Finally, the industrial and therapeutic value of recombinant PCB is considerable. Heterologous expression systems provide consistent, high-purity PCB suitable for pharmaceutical development, ensuring reproducibility while enabling innovation in formulations such as nanoparticles, cyclodextrins, and liposomes, as well as supporting intellectual property development.

PCB is a multitarget molecule with antioxidant, anti-inflammatory, mitochondrial-protective, and remyelination-supporting potential. Preclinical models of MS, ischemic stroke, and neurodegeneration have demonstrated its ability to modulate redox-sensitive pathways, dampen neuroinflammation, and improve functional outcomes. The heterologous production of PCB in engineered systems provides reproducible, high-purity, and scalable preparations for pharmaceutical development.

Key challenges include characterizing its pharmacokinetics, establishing BBB permeability, and defining a good laboratory practice-compliant toxicological profile. The regulatory pathway must clarify whether PCB will advance as a nutraceutical, a drug candidate, or potentially both.

Hence, PCB offers a unique opportunity to bridge natural product pharmacology with modern biotechnology, positioning it as a promising candidate for future neuroprotective and neurorepair strategies. In this regard, PCB may evolve from a nutraceutical curiosity into a clinically relevant neurotherapeutic.