Jafar Aghajani
1 
, Morteza Mirzaei
1 , Ali Choopani
1 , Hosna Abbasi
2 , Fatemeh Shakeri
1 , Ali Mohammad Latifi
1* 1 Applied Biotechnology Research Center, New Health Technologies Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
2 Department of Microbiology, Science and Research Branch, Islamic Azad University, Tehran, Iran
Abstract
Astaxanthin (AXT) is a valuable xanthophyll carotenoid extensively utilized across the nutraceutical, pharmaceutical, cosmetic, and aquaculture industries. While this high-demand compound is produced both synthetically and biologically, natural AXT derived from the microalga Haematococcus lacustris (formerly called Haematococcus pluvialis) offers superior bioavailability and safety profiles, dominating the high-value market segment. However, the current industrial reality is hampered by low yields under standard cultivation, significantly restricting commercial viability. This comprehensive review systematically summarizes the latest advancements (2020-2025) in achieving cost-effective and sustainable hyper-production of natural AXT from H. pluvialis. We critically evaluate both established methodologies (e.g., two-phase cultivation, stress induction) and emerging strategies, including CRISPR-Cas9 editing, electrogenetics, and the application of nano-based stressors. Recent studies highlight significant yield enhancements, with reports of 20-35% increases via gene knock-ins and mild electric stimulation, achieving concentrations up to 200 mg L⁻¹. Crucially, this work provides an integrative comparison of advanced genetic engineering tools, nano-based induction protocols, and hybrid cultivation systems, distinguishing it from previous reviews focused predominantly on environmental factor optimization. The analysis offers actionable, evidence-based insights for accelerating the transition from lab-scale innovation to scalable industrial bioprocesses, thereby reducing production costs and enhancing the overall sustainability of natural AXT supply.