EMERGING THERAPEUTIC APPROACHES FOR LIVER REGENERATION

ABSTRACT

Chronic liver disease and cirrhosis are major global health burdens, with limited therapeutic options beyond transplantation. This study aimed to characterize the clinical development landscape of liver regeneration therapies. We reviewed interventional trials registered on ClinicalTrials.gov as of September 18, 2025, using the search term “liver regeneration”. Eligible studies included Early Phase 1 through Phase 3 interventional trials. Trial characteristics were analyzed by phase, therapeutic modality, sponsor type, enrollment size, and geographic distribution. A total of 34 clinical trials were identified. The majority were early-stage studies, with 44% in Phase 1 and 35% in Phase 2; only 21% had progressed to Phase 3. Most trials were sponsored by academic or hospital-based institutions (82%), with limited industry involvement (12%). Geographically, activity was concentrated in India (29%) and China (21%), followed by Spain and other countries. Therapeutic approaches were diverse: cell therapies (24%), growth factors/biologics (26%), surgical/interventional techniques (6%), small molecules (9%), and other/unspecified (35%). Enrollment sizes ranged from 4 to 259 participants, with most trials enrolling fewer than 50 patients. Liver regeneration is an emerging but still early-phase field, dominated by academic-driven, small-scale exploratory studies. While cell therapies and biologics represent the most frequently tested modalities, clinical benefit remains uncertain. Larger randomized Phase 3 trials, standardized outcome measures, and stronger industry engagement will be essential to establish regenerative therapies as viable clinical options for patients with end-stage liver disease.

АННОТАЦИЯ

Хронические заболевания печени и цирроз являются серьезной глобальной проблемой здравоохранения, при этом терапевтические возможности ограничены трансплантацией. Целью данного исследования было охарактеризовать ландшафт клинической разработки терапий, направленных на регенерацию печени. Мы проанализировали интервенционные клинические исследования, зарегистрированные на ClinicalTrials.gov по состоянию на 18 сентября 2025 г., используя поисковый запрос «liver regeneration». Включались интервенционные исследования от ранней I фазы до III фазы. Характеристики исследований оценивались по фазе, терапевтической стратегии, типу спонсора, численности участников и географическому распределению. Всего было выявлено 34 клинических исследования. Большинство находилось на ранних стадиях: 44% на I фазе и 35% на II фазе; лишь 21% продвинулись до III фазы. Большинство исследований проводились академическими или клиническими учреждениями (82%), при ограниченном участии индустрии (12%). Географически активность концентрировалась в Индии (29%) и Китае (21%), затем следовали Испания и другие страны. Терапевтические подходы были разнообразны: клеточные терапии (24%), ростовые факторы/биологические препараты (26%), хирургические и интервенционные методики (6%), малые молекулы (9%) и прочие/неуточненные (35%). Размер выборки варьировал от 4 до 259 участников, при этом большинство исследований включало менее 50 пациентов. Регенерация печени является развивающейся, но пока еще ранней областью, где доминируют академически ориентированные, маломасштабные исследования. Несмотря на то, что клеточные терапии и биологические препараты представляют собой наиболее часто тестируемые подходы, их клиническая эффективность пока остается неопределенной. Для внедрения регенеративных технологий в клиническую практику потребуются более масштабные рандомизированные исследования III фазы, стандартизированные конечные точки и более активное участие индустрии.

Keywords: liver regeneration, clinical trials, cell therapy, growth factors, portal vein embolization, regenerative medicine.

Ключевые слова: регенерация печени, клинические исследования, клеточная терапия, ростовые факторы, эмболизация воротной вены, регенеративная медицина.

INTRODUCTION

Chronic liver disease and cirrhosis remain major global health challenges, contributing to nearly 2 million deaths annually worldwide [1]. Although the liver has a strong intrinsic capacity for regeneration, in advanced conditions such as cirrhosis, acute-on-chronic liver failure (ACLF), or following extended hepatectomy, this capacity is insufficient to restore function [2]. Liver transplantation continues to be the only definitive therapy; however, organ shortages, surgical complications, and the lifelong need for immunosuppression severely limit its accessibility [3].

These limitations have driven interest in regenerative strategies that can stimulate liver repair or augment residual function. Several approaches are under clinical investigation:

• Cell-based therapies, particularly mesenchymal stem cells (MSCs) and bone marrow-derived cells, which have shown immunomodulatory and hepatoprotective effects in both preclinical and clinical studies [4,5].
• Growth factors and biologics, such as granulocyte colony-stimulating factor (G-CSF) and recombinant growth hormone, which aim to mobilize progenitor cells and enhance endogenous repair [6].
• Surgical and interventional radiology techniques, including portal vein embolization (PVE) and associating liver partition and portal vein ligation for staged hepatectomy (ALPPS), which can accelerate hypertrophy of the future liver remnant before major resections [7,8].
• Small molecules and pharmacologic agents, which are emerging as potential modulators of fibrosis and vascular remodeling [9].

Recent reviews highlight the expansion of MSC-based therapies into multiple clinical trials, with encouraging safety data but variable efficacy outcomes [4]. Advances in mechanistic understanding of liver regeneration, including signaling pathways, metabolic reprogramming, and microenvironmental regulation, are also shaping next-generation therapies [2]. Meanwhile, regenerative surgery techniques such as ALPPS are under critical evaluation, balancing rapid hypertrophy with risks of increased morbidity [7,8].

Given this diversity, the present study systematically reviews interventional clinical trials in liver regeneration registered on ClinicalTrials.gov. Our aim is to describe trial characteristics by phase, modality, sponsorship, and geography, and to highlight opportunities and challenges for translating regenerative approaches into clinical practice.

MATERIALS AND METHODS

We compiled information on clinical trials from the ClinicalTrials.gov database on September 18, 2025. The search was restricted to studies investigating liver regeneration and limited to interventional trials in Early Phase 1, Phase 1, Phase 2, and Phase 3.

Only studies that were clearly focused on regenerative strategies for liver disease were retained. Trials that addressed unrelated therapeutic approaches or conditions were excluded from the dataset.

For consistency, trials labeled as “Early Phase 1” were included with Phase 1 studies, while “Phase 1/2” trials were also categorized under Phase 1, and “Phase 2/3” studies were counted with Phase 2.

Each record was reviewed to extract details on the following features: clinical phase, enrollment size, therapeutic category (cell-based, gene-based, biologic, biomaterial, or small molecule), mode of administration, sponsor type, and trial location.

This methodological approach followed the same principles as described previously for landscape analyses of ClinicalTrials.gov datasets [10].

RESULTS

A total of 34 interventional clinical trials investigating liver regeneration were identified in ClinicalTrials.gov as of September 18, 2025. Most studies were in the early stages of development, with 15 Phase 1 trials (44%) and 12 Phase 2 trials (35%). Only 7 trials (21%) had progressed to Phase 3. At the time of data extraction, 13 trials (38%) were listed as Completed, while another 13 trials (38%) had an Unknown status. Six studies (18%) were Not yet recruiting, and only two trials (6%) were actively recruiting participants. Academic and non-profit organizations accounted for the majority of activity, with 28 trials (82%) sponsored by institutions categorized as “Other.” In contrast, industry sponsors supported 4 trials (12%), and government-affiliated organizations accounted for 2 trials (6%). The largest number of trials were conducted in India (10 trials, 29%), followed by China (7 trials, 21%), and Spain (3 trials, 9%). Additional contributions came from South Korea, Indonesia, and Iran. Single studies were registered in Japan, Hong Kong, and Turkey. Three trials did not report a location. Analysis revealed a diverse portfolio: Cell therapies (24%), Growth factors/biologics (26%), Surgical/interventional techniques (6%), Small molecules (9%), and Other/unspecified (35%). Study sizes varied considerably. The smallest trial enrolled 4 participants, while the largest planned enrollment reached 259 participants. Most trials involved fewer than 50 patients, reflecting the exploratory and early-stage nature of this research area.

Figure 1. Distribution of liver regeneration clinical trials by therapy category and clinical phase

DISCUSSION

This analysis highlights that liver regeneration remains an emerging field, with the majority of registered trials concentrated in Phase 1 (44%) and Phase 2 (35%). The limited number of Phase 3 studies (21%) underscores the exploratory nature of this research and the need for more definitive trials to establish clinical efficacy. Small sample sizes and frequent “unknown” recruitment statuses further emphasize that translation into routine practice is still distant.

The dominance of India and China in trial activity (together nearly 50%) reflects both the high disease burden and the strong role of academic hospital networks in pioneering regenerative approaches. Comparable patterns have been reported in other analyses of global trial distribution, which note regulatory flexibility and high patient availability in these regions [1]. In contrast, Western countries remain underrepresented, possibly due to stricter regulations and greater reliance on established transplant programs. The heavy predominance of academic sponsorship (82%) compared to limited industry participation (12%) suggests that commercial investment in regenerative hepatology is still cautious.

The therapeutic diversity seen in our dataset reflects the experimental character of this field. Cell-based therapies remain the cornerstone, accounting for nearly a quarter of all studies. Recent systematic reviews confirm their good safety profile but highlight variability in efficacy, partly due to heterogeneity in cell sources, delivery routes, and patient populations [4,5]. Growth factors and biologics (26%), especially G-CSF, represent one of the few categories with Phase 3 activity, though evidence remains mixed, with some trials demonstrating improved survival in ACLF while others report minimal benefit [11,12].

Surgical and interventional approaches such as PVE and ALPPS are established in clinical practice to induce hypertrophy of the future liver remnant. Our findings confirm that only a small fraction of regeneration trials is surgical, yet these methods remain crucial bridges to safe hepatectomy. Recent mechanistic studies have clarified how ALPPS induces accelerated hypertrophy, but they also confirm higher morbidity compared with PVE [7,8]. This balance between efficacy and risk explains why surgical methods are often combined with pharmacologic or cell-based strategies in translational protocols.

Small molecules and pharmacologic modulators remain underrepresented (9%), but recent research suggests their potential role in fibrosis modulation and vascular remodeling [9].

Overall, the early findings suggest that liver regeneration strategies are generally safe and biologically active, but clear evidence of durable clinical benefit remains limited. Larger randomized trials, harmonized clinical endpoints, and stronger industry engagement will be critical to establish regenerative therapies as viable clinical options for patients with end-stage liver disease. By addressing these gaps, regenerative strategies could evolve from small-scale exploratory studies to viable alternatives or adjuncts to transplantation, fulfilling an urgent unmet need in patients with advanced liver disease.

References:

1. Devarbhavi H., Asrani S.K., Arab J.P., Nartey Y.A., Pose E., Kamath P.S. Global burden of liver disease: 2023 update // J. Hepatol. – 2023. – Vol. 79, № 2. – P. 516–537. – DOI: https://doi.org/10.1016/j.jhep.2023.03.017.
2. Ma X., Huang T., Chen X., Li Q., Liao M., Fu L., Huang J., Yuan K., Wang Z., Zeng Y. Molecular mechanisms in liver repair and regeneration: from physiology to therapeutics // Signal Transduct. Target. Ther. – 2025. – Vol. 10, № 1. – Article 63. – DOI: https://doi.org/10.1038/s41392-024-02104-8.
3. Kim W.R., Lake J.R., Smith J.M., Schladt D.P., Skeans M.A., Noreen S.M., Robinson A.M., Miller E., Snyder J.J., Israni A.K., Kasiske B.L. OPTN/SRTR 2017 annual data report: liver // Am. J. Transplant. – 2019. – Vol. 19, Suppl. 2. – P. 184–283. – DOI: https://doi.org/10.1111/ajt.15276.
4. Huang W-C., Li Y-C., Chen P-X., Ma K-S., Wang L-T. Mesenchymal stem cell therapy as a game-changer in liver diseases: review of current clinical trials // Stem Cell Res. Ther. – 2025. – Vol. 16, № 1. – Article 3. – DOI: https://doi.org/10.1186/s13287-024-04127-y.
5. Liu Z., Ren J., Qiu C., Wang Y., Zhang T. Application of mesenchymal stem cells in liver fibrosis and regeneration // Liver Res. – 2024. – Vol. 8, № 4. – P. 246–258. – DOI: https://doi.org/10.1016/j.livres.2024.11.004.
6. Chavez-Tapia N.C., Mendiola-Pastrana I., Ornelas-Arroyo V.J., Noreña-Herrera C., Vidaña-Perez D., Delgado-Sanchez G., Uribe M., Barrientos-Gutierrez T. Granulocyte-colony stimulating factor for acute-on-chronic liver failure: systematic review and meta-analysis // Ann. Hepatol. – 2015. – Vol. 14, № 5. – P. 631–641. – DOI: https://doi.org/10.1016/S1665-2681(19)30757-4.
7. Heil J., Schiesser M., Schadde E. Current trends in regenerative liver surgery: novel clinical strategies and experimental approaches // Front. Surg. – 2022. – Vol. 9. – Article 903825. – DOI: https://doi.org/10.3389/fsurg.2022.903825.
8. Du Y., Yang Y., Zhang Y., Zhang F., Wu J., Yin J. Unraveling enhanced liver regeneration in ALPPS: integrating multi-omics profiling and in vivo CRISPR in mouse models // Hepatol. Commun. – 2025. – Vol. 9, № 3. – P. e0630. – DOI: 10.1097/HC9.0000000000000630.
9. Cardinale V., Lanthier N., Baptista P.M., Carpino G., Carnevale G., Orlando G., Angelico R., Manzia T.M., Schuppan D., Pinzani M., Alvaro D. Cell transplantation-based regenerative medicine in liver diseases // Stem Cell Reports. – 2023. – Vol. 18, № 8. – P. 1555–1572. – DOI: https://doi.org/10.1016/j.stemcr.2023.06.005.
10. Iamukova L., Alferova E. Personalized cancer vaccines in the clinical trial pipeline // Asia-Pac. J. Clin. Oncol. – 2025. – Published online Aug 26. – DOI: https://doi.org/10.1111/ajco.70006.
11. Qiu B., Liang J.X., Romero Gómez M. The efficacy and safety of granulocyte colony-stimulating factor in the treatment of acute-on-chronic liver failure: a systematic review and meta-analysis // PLoS One. – 2023. – Vol. 18, № 11. – e0294818. – DOI: https://doi.org/10.1371/journal.pone.0294818.
12. Martin-Mateos R., González-Alonso R., Álvarez-Díaz N., Muriel A., Gaetano-Gil A., Ortega J.D., López-Jerez A., Tubio A.F., Albillos A. Granulocyte-colony stimulating factor in acute-on-chronic liver failure: systematic review and meta-analysis of randomized controlled trials // Gastroenterol. Hepatol. (Engl. Ed.). – 2023. – Vol. 46, № 5. – P. 350–359. – DOI: https://doi.org/10.1016/j.gastre.2023.05.001.