The technical foundation of the field rests on two reprogramming strategies. Integrative methods, which use retroviral or lentiviral vectors to deliver the classic quartet of factors—OCT4, SOX2, KLF4 and c-MYC—are efficient but insert themselves permanently into the genome, raising the specter of insertional mutagenesis and tumor formation. Non-integrative alternatives, including Sendai virus, episomal plasmids, synthetic mRNA and protein-based approaches, leave no genetic scars and are now favored for clinical translation, even though they tend to be less efficient and more expensive. The payoff is the ability to manufacture transgene-free, GMP-compliant cell lines suitable for personalized medicine and regenerative therapies, a goal that has come steadily closer over the review period.

What makes iPSCs so potent for drug discovery is their capacity to reproduce human disease in a dish. Patient-derived iPSCs can be coaxed into neurons, cardiomyocytes, hepatocytes or pancreatic beta cells that carry the exact genetic variants underlying a person’s illness, allowing researchers to study molecular mechanisms that animal models frequently misrepresent. This has proven particularly valuable for neurodegenerative disorders, cancer and metabolic conditions, where interspecies differences between mice and humans have derailed countless promising compounds. High-throughput screening campaigns can now run thousands of candidate drugs against disease-relevant human cells, identifying molecules that correct cellular pathologies rather than merely surviving toxicity filters designed around animal physiology.

The review highlights striking successes in drug repositioning, the rediscovery of new uses for existing medicines. Using patient-specific iPSC models, researchers identified statins as potential treatments for achondroplasia and the anticonvulsant ezogabine as a candidate therapy for amyotrophic lateral sclerosis. Screens against familial dysautonomia and ALS have similarly surfaced compounds that would have been difficult to find through conventional pipelines. These platforms are increasingly woven into clinical trials themselves, serving as pre-screening tools that predict how individual patients will respond to therapy, cutting down on trial-and-error prescribing and reducing adverse effects by matching the right drug to the right genetic background before the first dose is ever administered.

Nowhere is the approach more consequential than in Alzheimer’s disease, a condition that has devoured decades of research funding and an unbroken series of failed clinical trials. iPSC-derived neurons and glial cells now replicate the disease’s signature pathologies in vitro, including amyloid-beta accumulation and tau phosphorylation. High-content screens using these models flagged the anti-inflammatory drug cromolyn and antiparasitic avermectins as potential amyloid-lowering agents, while statins emerged as modifiers of phosphorylated tau. Tri-culture systems combining neurons, astrocytes and microglia have illuminated the glial dimension of neurodegeneration, and single-cell RNA sequencing has mapped gene expression changes across disease progression, surfacing new biomarkers. CRISPR/Cas9 editing of iPSC lines derived from patients with PSEN1 and PSEN2 mutations has allowed precise validation of therapeutic targets such as BACE1 and MAPT, and clarified unexpected links between cholesterol biosynthesis and amyloid precursor protein dysfunction.

Diabetes research has followed a parallel trajectory. Differentiation protocols guided by the transcription factors PDX1, NKX6.1 and Ngn3 now generate glucose-responsive, insulin-secreting beta-like cells from iPSCs, and recent studies have shown these cells can reverse hyperglycemia in streptozotocin-induced diabetic mice. Three-dimensional organoid systems have sharpened the maturity and glucose responsiveness of the derived cells, better approximating native pancreatic islets. Beyond replacement therapy, patient-derived iPSCs have been differentiated into endothelial cells that model diabetic vascular dysfunction, a screening platform that identified angiotensin receptor blockers as candidates for restoring endothelial function. Encapsulation of iPSC grafts in elastin-like recombinamers has shown promise for immunoprotection, addressing one of the central obstacles to durable cell replacement in type 1 diabetes.

In arthritis, the technology has produced some of the most inventive therapeutic engineering to date. CRISPR-engineered iPSC-derived macrophages have been designed to sense tumor necrosis factor-alpha and respond by autonomously secreting anti-inflammatory biologics such as soluble TNF receptor 1, quelling joint inflammation and bone erosion in murine models. iPSC-derived extracellular vesicles have reduced IL-1beta-driven chondrocyte death in osteoarthritis models while suppressing the cartilage-degrading enzymes ADAMTS5 and MMP13. Even more strikingly, vesicles from anti-inflammatory M2 macrophages can reprogram pro-inflammatory M1 macrophages within inflamed synovial tissue with efficiencies exceeding ninety percent, restoring a critical immune balance and boosting production of IL-10 and other tissue-protective cytokines. The iPSC secretome itself—exosomes, vesicles and growth factors—is emerging as a drug class in its own right, offering regenerative and immunomodulatory effects without the risks of transplanting live cells.

Cancer modeling has been equally transformed. Reprogramming tumor cells back to a pluripotent state can erase epigenetic damage, such as the hypermethylation of tumor suppressor genes in glioblastoma multiforme, creating a window into how malignancies originate. iPSC-based chimeras have modeled osteosarcoma and pancreatic ductal adenocarcinoma, while transient expression of the oncogene MLL-AF4 in iPSCs has reproduced B-acute lymphoblastic leukemia, and iPSCs carrying germline TP53 mutations have illuminated osteosarcoma formation in Li-Fraumeni syndrome. Organoids derived from iPSCs recreate the three-dimensional architecture of tumors, offering a far more faithful stand-in for the tumor microenvironment than flat cultures, and when combined with patient-derived xenografts they support biomarker discovery and pharmacological testing in vivo.

None of this has been easy. The review is candid about the field’s technical debts: genetic instability accumulates during reprogramming and long-term expansion, and even minor mutations introduced during cell generation can confer tumorigenic potential. Differentiation protocols vary between laboratories, producing inconsistent disease models and irreproducible drug response data. The costs of growth factors and specialized media under GLP and GMP standards are punishing, and residual undifferentiated cells raise unresolved immunogenicity concerns. Ethical questions compound the technical ones—donors are often inadequately informed about whether their cells may be used in human-animal chimera studies or germline-related research, incidental genetic findings are disclosed inconsistently, and regulatory oversight of cell therapies remains fragmented across jurisdictions, leaving openings for unproven treatments to reach vulnerable patients.

The authors’ prescriptions are pragmatic. They call for standardized differentiation protocols, shared reference cell lines and validation criteria to make results comparable across the field; deeper collaboration among academia, biotechnology and pharmaceutical companies and regulators to build scalable, compliant products; expanded investment in automation and machine learning to predict and control differentiation outcomes; transparent consent frameworks that spell out the full scope of possible research uses; long-term safety monitoring with centralized tracking of patients receiving iPSC-derived therapies; and sustained public engagement to build the trust on which the entire enterprise depends. If those foundations hold, the five years from 2020 to 2024 may be remembered as the period when drug development finally began to run on human biology rather than approximation—and the diseases that have resisted medicine longest may at last face models that truly resemble them.

Subject of Research: Applications of induced pluripotent stem cells in novel drug development from 2020 to 2024

Article Title: Recent progress in the use of induced pluripotent stem cells in novel drug development over the past 5 years (2020–2024)

Article References: Moseki, M. C., Makhzoum, A., Masisi, K., & Gaobotse, G. (2025). Recent progress in the use of induced pluripotent stem cells in novel drug development over the past 5 years (2020–2024). Discover Biotechnology, 2(1), Article 33. https://doi.org/10.1007/s44340-025-00042-x

Image Credits: AI Generated

DOI: 10.1007/s44340-025-00042-x

Keywords: induced pluripotent stem cells, iPSCs, drug discovery, disease modeling, Alzheimer's disease, diabetes, arthritis, cancer, personalized medicine, CRISPR, organoids, high-throughput screening