Optical imaging unveils morphological heterogeneity at the hepatic lobule level during metabolic dysfunction-associated fatty liver disease progression [Invited].

Hepatic lobules constitute the fundamental structural and functional units of the liver, which are essential for maintaining microcirculatory homeostasis, barrier integrity, and metabolic clearance. Optical imaging techniques, including photoacoustic microscopy (PAM) and near-infrared-II (NIR-II) fluorescence imaging, have been extensively employed to investigate liver structure and function. However, few studies have specifically addressed the structural and functional heterogeneity at the lobular level. In this study, we developed a dual-modal approach combining high-resolution PAM and dynamical NIR-II fluorescence imaging to assess hepatic lobular vascular structure, permeability, and metabolic function in the models of metabolic dysfunction-associated fatty liver disease (MAFLD). PAM imaging revealed progressive vascular disorganization and increased morphological heterogeneity during fibrosis, while Evans blue (EB) permeability analysis showed elevated regional differences in vascular permeability. NIR-II imaging further demonstrated reduced hepatic lobular functional reserve in livers with hepatic steatosis. This approach underscores hepatic lobular heterogeneity during MAFLD progression. Collectively, this study presents a hepatic lobule-level optical imaging framework that enables integrated assessment of microstructural remodeling, vascular permeability, and metabolic function, providing new insights into intra-lobular heterogeneity during the progression of MAFLD.