Navigating the New Therapeutic Landscape: Innovative Strategies for Overcoming Resistance and Degeneration

Abstract

Recent technological advancements and environmental shifts have reshaped the therapeutic landscape of human diseases, driving a transition from merely understanding pathogenesis to developing precise and targeted therapeutic solutions. While the 2025 Special Issue focused on identifying emerging risk factors, the 2026 Special Issue (Vol. 34, No. 1) pivots toward concrete methodological innovations and advanced therapeutic interventions. This issue presents a curated collection of ten distinguished articles organized around three core themes. First, in the field of oncology and drug resistance, studies investigate transglutaminase 2 (TG2)-mediated autophagy and ferroptosis as strategies to overcome therapeutic resistance, alongside advances in CAR-T cell engineering and the integration of artificial intelligence (AI) with robotic surgery to enable precision medicine. Second, addressing degenerative and metabolic diseases, contributions elucidate the role of Wnt/β-catenin signaling in osteoporosis, recent therapeutic advances in knee osteoarthritis, mechanisms underlying drug-induced senescence, and the application of gene-editing technologies in iPSC-derived hepatic models. Finally, investigations into the neuro–immune axis highlight the dual roles of adaptive immunity in Alzheimer’s disease and evaluate novel pharmacological modulators targeting the kynurenine–aryl hydrocarbon receptor (AhR) axis. Collectively, this Special Issue delivers groundbreaking insights and innovative strategies aimed at restoring biological homeostasis and overcoming intractable diseases.

INTRODUCTION

Rapid technological advancements and evolving environmental conditions continue to reshape the spectrum of human diseases, necessitating corresponding advances in therapeutic strategies. In the 2025 Special Issue (Vol. 33, No. 1), Biomolecules & Therapeutics identified key emerging themes for 21st-century diseases, with a particular emphasis on the pathological consequences of environmental exposures and systemic metabolic dysregulation (Ko and Lee, 2024). The 2025 Special Issue offered a comprehensive overview of seven critical topics: “Obesity” and “Metabolic dysfunction-associated steatotic liver disease (MASLD),” focusing on GLP-1 agonists and AMPK inhibitors (An et al., 2024; Kim and Kim, 2024); “Kidney Disease” treated with natural compounds (Natesan and Kim, 2024); and “Osteoarthritis,” highlighting the regenerative potential of stem cells (Lee et al., 2024). Furthermore, it explored the “Cancer-Nerve Intersection” (Baek, 2024), the role of “Probiotics” in neurodegenerative diseases (Kim et al., 2024), and the emerging immunological threat of “Micro- and Nanoplastics” (Dan et al., 2024).

Building upon this foundational understanding of disease phenomenology, the 2026 Special Issue (Vol. 34, No. 1) pivots toward precise and fundamental “Therapeutic Interventions.” While the 2025 issue centered on identifying causes and risk factors, the keywords for 2026—”Drug Resistance,” “Gene Editing,” “AI-driven Precision Medicine,” and the “Neuro-Immune Axis”—are oriented toward concrete solutions and technological innovations. The articles presented in this issue represent the forefront of next-generation biomolecular medicine, moving beyond mere symptom alleviation to overcome evolutionary resistance and restore biological homeostasis.

OVERCOMING RESISTANCE AND ADVANCING PRECISION IN ONCOLOGY

The development of drug resistance and the need for precision therapies remain formidable challenges in oncology, as emphasized by recent high-profile studies. A 2020 study in Nature highlighted that resistance to targeted therapies is often driven by non-genetic adaptive mechanisms, such as transcriptional plasticity and metabolic reprogramming (Marine et al., 2020). Furthermore, targeting unique metabolic vulnerabilities in drug-resistant cancer cells, such as ferroptosis induction, offers a powerful new therapeutic avenue (Jiang et al., 2021).

In this issue, Kim (2026) provide a compelling analysis of transglutaminase 2 (TG2)-mediated autophagy as a primordial chaperone mechanism to overcome acquired drug resistance. Complementing this, Joo et al. (2026) explore the molecular mechanisms of ferroptosis as a strategic target to bypass resistance pathways. In the realm of immunotherapy, Ha and Seong (2026) present novel screening methods for advancing CAR-T cell engineering, offering promising avenues for enhanced efficacy. Furthermore, Deng et al. (2026) demonstrate the integration of molecular diagnostics and artificial intelligence (AI) in robotic BABA thyroidectomy, marking a leap forward in precision surgery (Fig. 1).

Fig. 1.

From resistance to precision: The evolution of oncology in 2026. This schematic illustrates the transition from current therapeutic challenges to future precision medicine, highlighting key findings in Biomolecules & Therapeutics (Vol. 34, No. 1). (A) The landscape of drug resistance driven by metabolic and non-genetic mechanisms. (B) Four innovative strategies in this issue acting as engines of progress: targeting TG2-mediated autophagy (Kim, 2026), inducing ferroptosis (Joo et al., 2026), advancing CAR-T engineering (Ha and Seong, 2026), and robotic AI surgery (Deng et al., 2026). (C) A future vision integrating AI and multi-omics for dynamic, adaptive therapies (AI, artificial intelligence; CAR-T, chimeric antigen receptor T-cell; TG2, transglutaminase 2).

These contributions reinforce the journal’s active engagement in this field. Biomolecules & Therapeutics has consistently published significant research on these topics, including recent explorations of drug resistance mechanisms (Kang et al., 2025) and novel therapeutic strategies targeting ferroptosis (Jung et al., 2023; Li et al., 2025). Moreover, our recent issues have highlighted advancements in CAR-T cell therapy for solid tumors (Moon and Song, 2025) and the growing role of AI in precision medicine (Lee et al., 2021), establishing a continuum of research that bridges past findings with the current issue’s breakthroughs.

Looking ahead, the future of oncology lies in moving beyond the “one-mutation, one-drug” paradigm towards a more holistic understanding of tumor evolution. The integration of multi-omics data with AI will be crucial for predicting drug resistance trajectories and designing dynamic, adaptive combinatorial therapies (Swanton, 2025). We anticipate that future studies in Biomolecules & Therapeutics will focus on elucidating these complex evolutionary dynamics.

MOLECULAR INSIGHTS INTO DEGENERATIVE AND METABOLIC DISEASES

Understanding the molecular basis of tissue degeneration and metabolic disorders has become increasingly critical as the global burden of aging-related diseases continues to rise. Recent reviews have underscored that interconnected pathways involving cellular senescence, chronic inflammation, and metabolic dysregulation serve as central drivers of age-related pathologies, including osteoporosis and osteoarthritis (Sandra, 2025). A recent review further highlighted the pivotal role of senescence-associated secretory phenotypes (SASP) in promoting tissue deterioration and driving secondary pathological processes (Ajoolabady et al., 2025). Addressing these challenges, Cao and Wang (2026) elucidate the critical roles of Wnt/β-catenin signaling in osteoporosis pathogenesis and its intervention via natural compounds, while Hossain et al. (2026) summarize recent therapeutic advances for knee osteoarthritis. Investigating drug-induced toxicity, Yun et al. (2026) reveal how β-catenin and AMPK/AKT/FOXO signaling mediate doxorubicin-induced senescence and lipid accumulation in myoblasts. Additionally, Lim and Kim (2026) highlight the potential of gene editing in pluripotent stem cell-derived hepatic cells for modeling liver disease and therapeutic development (Fig. 2).

Fig. 2.

From tissue degeneration to molecular restoration (Vol. 34, No. 1). This schematic illustrates the transition from age-related pathology to homeostasis. (A) Degeneration driven by cellular senescence (SASP) and metabolic dysregulation. (B) Targeted interventions presented in this issue: Wnt/β-catenin activation for osteoporosis (Cao and Wang, 2026); strategies against knee osteoarthritis (Hossain et al., 2026); AMPK/AKT/FOXO modulation mitigating doxorubicin-induced senescence (Yun et al., 2026); and iPSC gene editing for liver disease modeling (Lim and Kim, 2026). (C) collective outcome leading to geroprotection and extended healthspan (AMPK, AMP-activated protein kinase; iPSC, induced pluripotent stem cell; SASP, senescence-associated secretory phenotype).

This focus on tissue homeostasis aligns with the journal’s ongoing discourse. Some publications in Biomolecules & Therapeutics have covered the therapeutic potential of Wnt signaling in bone formation (Pengjam et al., 2016) and molecular progress in osteoarthritis treatment (Lee et al., 2024).

The future direction for degenerative and metabolic disease research points towards therapeutic strategies that target the fundamental drivers of aging. A recent report emphasizes the potential of senolytics and geroprotectors to prevent multiple age-related comorbidities simultaneously (Carmona-Gutierrez et al., 2025). Future contributions are expected to explore the translation of these molecular insights into clinical applications for promoting healthy longevity.

THE NEURO-IMMUNE AXIS AND EMERGING THERAPEUTIC STRATEGIES

The complex interplay between the immune system and the nervous system is a rapidly evolving frontier in neuroscience. A recent study demonstrated that specific adaptive immune cells can access the brain and profoundly influence the progression of neurodegenerative diseases, including Alzheimer’s disease (Gate et al., 2020). The aryl hydrocarbon receptor (AhR), previously recognized primarily as a mediator of environmental toxicity, has been re-evaluated as a key regulator of innate and adaptive immunity, emerging as a promising therapeutic target for treating cancer and autoimmune diseases. With the recent approval of the AhR agonist tapinarof, the development of diverse AhR-targeting immunomodulatory therapeutics and related clinical trials are actively underway (Polonio et al., 2025).

Building on this knowledge, Ahn and Shin (2026) investigate the dual roles of adaptive immunity in Alzheimer’s disease, discussing its implications for both neurodegeneration and neuroprotection. Finally, Cha et al. (2026) present a preclinical pharmacological and toxicological evaluation of SB5794, a novel modulator of the Kynurenine–AhR axis, expanding our arsenal of bioactive agents (Fig. 3).

Fig. 3.

Neuro-immunology and novel pharmacological frontiers. This schematic illustrates the evolving understanding of neuro-immune interactions (Vol. 34, No. 1). (A) The neuro-immune landscape and targeted interventions. Adaptive immune cells infiltrate the Alzheimer’s disease (AD) brain, where Ahn and Shin (2026) propose strategies to balance their dual roles in neuroprotection and neurodegeneration. Concurrently, the kynurenine–aryl hydrocarbon receptor (AhR) axis drives neuroinflammation, a pathway targeted by the novel modulator SB5794 (Cha et al., 2026). (B) Future horizon: The gut–immune–brain axis. Emerging research highlights how gut metabolites regulate this tripartite communication, shaping the future of neuro-immunological therapeutics (BBB, blood–brain barrier; AhR, aryl hydrocarbon receptor).

These contributions reinforce the journal’s established leadership in neuro-immunological research. Biomolecules & Therapeutics has consistently explored the systemic versatility of AhR signaling beyond toxicology, such as its role in skin aging (Jang et al., 2019; Kim et al., 2020), while also highlighting the gut-brain axis through studies on the therapeutic potential of probiotics and flavonoids in neurodegeneration (Kim et al., 2024; Xu et al., 2025). Furthermore, recent issues have deepened our molecular understanding of Alzheimer’s pathology: Oh et al. identified PLXDC2 as a microglial regulator that exacerbates disease by impairing amyloid-β phagocytosis (Oh et al., 2025), while Campomayor et al. elucidated how extracellular heme drives oxidative stress and blood-brain barrier dysfunction in neurodegenerative disorders (Campomayor et al., 2025).

Moving forward, the field is poised to unravel the “Gut-Immune-Brain axis.” A recent article revealed how specific gut metabolites can modulate neuroinflammation and influence neurodegenerative disorders (Cryan et al., 2020; Ugwu et al., 2025). We foresee that future research published in Biomolecules & Therapeutics will increasingly focus on decoding this trilateral communication.

CONCLUSION AND PERSPECTIVE

Through this 2026 Special Issue, we have witnessed multifaceted efforts to understand and control the evolutionary resistance of cancer, tissue degeneration associated with aging, and the complex dialogue between the brain and the immune system. Biomolecular medicine must now advance beyond the “One Target, One Drug” paradigm toward “Systemic Integrated Control.”

Looking ahead, the integration of multi-omics data with AI will enable the prediction of individual disease evolutionary trajectories, paving the way for Adaptive Therapy strategies that preemptively block resistance. Furthermore, with the advancement of Geroscience, which views aging itself as a treatable condition, anti-aging strategies such as senolytics are expected to enter clinical practice, significantly extending healthy lifespans. Finally, decoding macroscopic communication networks, such as the “Gut-Immune-Brain Axis,”—as evidenced by recent discoveries linking gut metabolites to neuroinflammation—will be the key to conquering intractable neurological disorders.

Biomolecules & Therapeutics remains committed to standing at the forefront of this scientific progress, serving as a vital bridge connecting fundamental research discoveries to clinical innovation.