Hyaluronic acid (HA), which is also known as hyaluronan or vitreous uric acid, represents a linear glycosaminoglycan with high molecular weight (MW). Its structure comprises a disaccharide repeating unit composed of UDP-glucuronic acid (UDP-GlcUA) and UDP-N-acetyl glucosamine (UDP-GlcNAc), which are linked alternately by β-(1–3) and β-(1–4) glycosidic bonds (Fig. 1) [1,2]. HA is the most hydrophilic substance known in nature, which demonstrates the remarkable capacity to bind water by approximately 1000 times its own weight [3]. It possesses distinctive characteristics such as high hygroscopicity, viscoelasticity, biocompatibility, non-immunogenicity, and biodegradability without generating toxic byproducts [4]. Given that HA is distributed widely in the interstitial tissues of various vertebrates and is present in certain bacterial capsules, it actively participates in essential metabolic and physiological processes [[5], [6], [7]]. The MW of HA varies significantly based on its source and processing method, and it ranges from <1000 Da to several million Da. Notably, HA of different MWs exhibits diverse properties and functionalities [[8], [9], [10]]. High-MW HA (HMW-HA) is extensively applied commercially in ophthalmology, orthopedics, wound healing, and cosmetics. Conversely, low-MW HA (LMW-HA), which are more readily absorbed by the body, plays a pivotal role in the development of cross-linked HA products and chronic wound healing.

The broad applications of HA in the food, cosmetic, and pharmaceutical industries have led to a burgeoning market demand, which exhibits a consistent upward trajectory [11]. Along with the increasing number of applications of HA, the market share tends to grow over the years. The global market size for HA is projected to reach USD 16.8 billion by 2030, which expands at a compound annual growth rate of 7.58 %, as reported by Grand View Research, Inc. [12]. At present, industrial HA production primarily relies on microbial fermentation. While significant research has been directed toward optimizing fermentation conditions to augment HA yield, progress appears to be reaching a plateau. By leveraging extensive insights into microbial polysaccharide biosynthetic pathways and associated genes, the construction of genetically engineered bacteria capable of producing HA has emerged as a focal area for research and development. These efforts aim to enhance yield and regulate MW and have yielded promising outcomes.

In recent years, numerous reviews have provided comprehensive overviews of HA production, examining the field from the vantage points of genetic engineering strategies and molecular weight considerations [3,13]. Despite the existence of these prior reviews, research in this domain has continued to progress rapidly. This article aims to spotlight recent advancements in the field, with a particular emphasis on the heterologous expression of hyaluronic acid aimed at mitigating the potential pathogenicity of Streptococcus. Furthermore, it delves into the augmentation of hyaluronic acid production and the modulation of molecular weight through the reconfiguration of energy metabolism pathways and cell membrane engineering in recent research. A critical analysis is provided regarding the challenges faced and the molecular biology-based strategies implemented over recent years for microbial HA production. The aim is to offer a valuable reference for future initiatives in the field of HA production.