Liver regeneration has been studied for many decades, and the mechanisms underlying regeneration of normal liver following resection are well described. However, no less relevant is the study of mechanisms that disrupt the process of liver regeneration. First of all, a violation of liver regeneration can occur in the presence of concomitant hepatic pathology, which is a key factor reducing the liver’s regenerative potential. Understanding these mechanisms could enable the rational targeting of specific therapies to either reduce the factors inhibiting regeneration or to directly stimulate liver regeneration. This review describes the known mechanisms of normal liver regeneration and factors that reduce its regenerative potential, primarily at the level of hepatocyte metabolism, in the presence of concomitant hepatic pathology. We also briefly discuss promising strategies for stimulating liver regeneration and those concerning methods for assessing the regenerative potential of the liver, especially intraoperatively.

The extracellular matrix (ECM) plays an important role in regulation of many aspects of tumor growth and response to therapies. However, the specifics of the interaction of chemotherapeutic agents with cancer cells in the presence of collagen, the major component of ECM, is still poorly investigated. In this study, we explored distribution of doxorubicin (DOX) and its effects on cancer cells’ metabolism in the presence of collagen with different structures in 3D models. For this, a combination of second harmonic generation imaging of collagen and multiphoton fluorescence microscopy of DOX, and metabolic cofactor NAD(P)H was used. It was found that collagen slowed down the diffusion of DOX and thus decreased the cellular drug uptake. Besides nuclei, DOX also targeted mitochondria leading to inhibition of oxidative phosphorylation, which was more pronounced in the cells growing in the absence of collagen. As a result, the cells in collagen displayed better viability upon treatment with DOX. Taken together, our data illustrate that tumor collagen contributes to heterogeneous and sub-optimal response to DOX and highlight the challenges in improving drug delivery and efficacy.

To reduce the risk of post-hepatectomy liver failure in patients with hepatic pathologies, it is necessary to develop an approach to express the intraoperative assessment of the liver’s regenerative potential. Traditional clinical methods do not enable the prediction of the function of the liver remnant. Modern label-free bioimaging, using multiphoton microscopy in combination with second harmonic generation (SHG) and fluorescence lifetime imaging microscopy (FLIM), can both expand the possibilities for diagnosing liver pathologies and for assessing the regenerative potential of the liver. Using multiphoton and SHG microscopy, we assessed the structural state of liver tissue at different stages of induced steatosis and fibrosis before and after 70% partial hepatectomy in rats. Using FLIM, we also performed a detailed analysis of the metabolic state of the hepatocytes. We were able to determine criteria that can reveal a lack of regenerative potential in violated liver, such as the presence of zones with reduced NAD(P)H autofluorescence signals. Furthermore, for a liver with pathology, there was an absence of the jump in the fluorescence lifetime contributions of the bound form of NADH and NADPH the 3rd day after hepatectomy that is characteristic of normal liver regeneration. Such results are associated with decreased intensity of oxidative phosphorylation and of biosynthetic processes in pathological liver, which is the reason for the impaired liver recovery. This modern approach offers an effective tool that can be successfully translated into the clinic for express, intraoperative assessment of the regenerative potential of the pathological liver of a patient.

The presence of molecular mutations in colorectal cancer (CRC) is a decisive factor in selecting the most effective first-line therapy. However, molecular analysis is routinely performed only in a limited number of patients with remote metastases. We propose to use tissue stiffness as a marker of the presence of molecular mutations in CRC samples. For this purpose, we applied compression optical coherence elastography (C-OCE) to calculate stiffness values in regions corresponding to specific CRC morphological patterns (n = 54). In parallel to estimating stiffness, molecular analysis from the same zones was performed to establish their relationships. As a result, a high correlation between the presence of KRAS/NRAS/BRAF driver mutations and high stiffness values was revealed regardless of CRC morphological pattern type. Further, we proposed threshold stiffness values for label-free targeted detection of molecular alterations in CRC tissues: for KRAS, NRAS, or BRAF driver mutation—above 803 kPa (sensitivity—91%; specificity—80%; diagnostic accuracy—85%), and only for KRAS driver mutation—above 850 kPa (sensitivity—90%; specificity—88%; diagnostic accuracy—89%). To conclude, C-OCE estimation of tissue stiffness can be used as a clinical diagnostic tool for preliminary screening of genetic burden in CRC tissues.

Chronic liver diseases are a rapidly growing threat to global health, causing approximately 2 million deaths annually—half from complications of cirrhosis and half from viral hepatitis and hepatocellular carcinoma. Despite this, effective diagnostic and therapeutic options remain limited, prompting an urgent need for novel translational strategies. Gene-based therapeutics have emerged as a promising solution compared to conventional treatments. This review highlights the therapeutic potential of delivering nucleic acid drugs using nanoengineered materials, which take advantage of the liver’s unique anatomical and physiological characteristics. We overview the liver physiology and function, and the underlying mechanisms of gene therapy—including gene augmentation, gene silencing, and gene editing. Special attention is given to current strategies and mechanisms of gene therapy. Furthermore, we discuss the clinical translation, benefits, and limitations of gene-based approaches in treating the most widespread liver diseases and pathologies such as nonalcoholic fatty liver disease, hepatic inflammation, hepatitis, and fibrosis. By addressing the current challenges and opportunities, this review underscores the transformative potential of nanoengineered gene therapeutics in advancing liver disease treatment and shaping the future of precision hepatology.

Molecular diagnostics based on small non-coding RNA molecules (in particular microRNA) is a new direction in modern biomedicine and is considered a promising method for identification of a wide range of pathologies at an early stage, clinical phenotype assessment, as well as monitoring the course of the disease, evaluation of therapy efficacy and the risk of the disease recurrence. Currently, the role of microRNAs as the most important epigenetic regulator in cancer development has been proven within the studies of normal and pathogenic processes. However, currently, there are insignificant studies devoted to studying the role of microRNAs in functioning of other organs and tissues, as well as to development of possible therapeutic approaches based on microRNAs. A huge number of metabolic processes in the liver are controlled by microRNAs, which creates enormous potential for the use of microRNAs as a diagnostic marker and makes it a target for therapeutic intervention in metabolic, oncological, and even viral diseases of this organ.This review examines various aspects of biological functions of microRNAs in different types of liver cells. Both canonical and non-canonical pathways of biogenesis, epigenetic regulation mediated by microRNAs, as well as the microRNAs role in intercellular communication and the course of viral diseases are shown. The potential of microRNAs as a diagnostic marker for various liver pathologies is described, as well as therapeutic approaches and medicines based on microRNAs, which are approved for clinical use and currently being developed.