Mechanopharmacology

We review the articles in the themed section on the concept of mechanopharmacology, the bidirectional impacts of extracellular and cellular biomechanics on drug action and vice versa. This concept has been brought to a higher priority in drug discovery and development by extensive recent changes in the regulatory and funding landscape, which are accelerating the adoption of novel approach methodologies (NAMs) including microphysiological systems (MPSs). In this section, papers presented at the World Congress of Pharmacology 2023 in Glasgow have been presented as reviews, mini-reviews and commentaries. Key messages include the need to use biomechanically appropriate settings to avoid confounding analyses of drug activity and to consider the impact of the composition of extracellular matrix when designing MPS microenvironments. In the post FDA modernisation Act 2.0 era (Stewart et al., 2023), there will be an increasing reliance on novel approach methodologies (NAMs), including the use of microphysiological systems (MPSs) for drug discovery and development. Indeed, the NIH policy reform in 2025 prohibiting the funding of research projects based exclusively on animal studies, together with the FDA release of a 5-year roadmap for the replacement of animals in the development of antibody-based therapeutics, underscores escalating policy and funding drivers that are expected to accelerate the adoption of MPSs and NAMs (which also include in silico and an in chemico methodologies) (Sunderic et al., 2025). The UK governments science minister and clinical pharmacologist, Lord Vallance, has recently announced the resourcing of a series of initiatives to accelerate the phase-out of selected animal testing, with, for example, animal-based Botox testing scheduled to end by 2027 and dog and non-human primate DMPK studies slated for reduction by 2030. These developments are influenced by increasing evidence of the fidelity of NAMs, recognition of the limitations of certain animal models, cost and efficiency pressures on biomedical research and concerns for animal welfare. Notwithstanding these considerations, there is an ethical imperative to ensure that NAMs are fit for purpose to support health and well-being across the domains of drug development and market approval, food and cosmetic safety and environmental safety more broadly. The preclinical application of the mechanopharmacology concept holds that the assay setting should reflect the biomechanical environment of the tissues, which are targeted by the compound class under investigation (Krishnan et al., 2016). We consider that this concept takes on increased significance with the UK-, FDA- and NIH-driven regulatory and funding changes outlined above. The mechanopharmacology theme has been elaborated in symposia at WCP2018 (World Congress of Pharmacology) and again at WCP2023, the latter having generated the themed section of four invited reviews and an original study that are the focus of this editorial. The mechanopharmacology concept is considered broadly in a review by Zielinski et al. (2024) who highlight a wide range of mechanical cues that have profound influences on cell function including flow-induced shear, the less well considered but pervasively important circadian physiology and most prominently, the modulus of the microenvironment. Technologies to effect dynamic strain are considered as are biophysically engineered biomaterials to achieve variable moduli. We have recently shown that low hydrogel stiffness can render transforming growth factor beta nonfibrogenic in human lung fibroblasts (Berhan et al., 2025). Our specific approach to in vitro circadian entrainment (Fustin et al., 2019; Gao et al., 2022) is discussed with respect to enabling technologies that included a multiplexed microfluidic pump (Gao et al., 2022), biosensors (Yang et al., 2024) and the use of a plasma-like medium (Zhang et al., 2024) that collectively enable not only circadian entrainment but allow for a constancy in the metabolite composition of the cell culture environment (Stewart et al., 2025). Zielinski et al. also review microfluidic-based models used for drug screening for efficacy and safety/toxicology features. The pressurised nature of microfluidics chamber represents a key difference with the open-well environments, with each approach having distinct advantages and limitations. The disconnection between in vitro culture-based tumour biology studies and the clinical translational environment in which these agents need to show efficacy was introduced by Tharp (2024) provocative question ‘Have plastic culture models prevented the discovery of effective cancer therapeutics’. This commentary goes further than just asserting that stiff plastic culture environments may have qualified agents for progression that subsequently fail in the clinic, to also focus on the false negatives that may be generated by use of a biomechanically inappropriate environment for cell-based assays. Tharp draws attention to the prominence of stress fibre formation in tumour cell lines cultured on plastic compared with their sparsity in solid tumours. The article highlights that the actin cytoskeletal cables interconnected with their counterpart microtubule struts are often implicated in chemotherapy resistance. Pathways implicated include transcription factors far down stream of integrins and focal adhesion kinases, including yes-associated protein (Yap). Thus, drugs that target such structures or their downstream effectors should be evaluated in a range of morphologies and biomechanical environments to better underwrite the predictive value of the assay systems. Consistent with this view, we recently identified tumour organoid culture in physiological stiffness matrigel was accompanied by extensive proteomic changes, reduced chemotherapy potency at Cmax concentrations and specific modulation of tubulin isoforms implicated in paclitaxel resistance (Zhang et al., 2024). Buning and Reckzeh (2025) continue the same theme of mechanically appropriate assay settings in a mini-review of the use of patient-derived organoids (PDOs) in drug development, focussing again on anti-tumour drug screening. Much cancer research is conducted on cell lines that have been in culture for many years and exhibit genetic instability rendering results of potentially low reproducibility. In contrast, literature is cited supporting the predictive value of tumour-derived PDOs, which show high correlation with chemotherapy or targeted cancer therapy responses in the PDO donor. Their discussion also raises the important issue of standardisation of such assays, an area of high priority, which is now to be supported in part by the recently announced NIH-funded Standardized Organoid Modelling Centre. An original paper by Mu et al. (2025) documented the effects of sphingosine 1 phosphate receptor antagonist in a preclinical model of pulmonary fibrosis induced by bleomycin in the mouse, adding to the many targets that have been qualified by this model. The study is notable for having used CT scanning among other more commonly applied measures to evaluate the extent of fibrosis. The relationship between ageing and tissue stiffness was canvassed by HaiYang et al. (2025) in a mini-review that extended to consideration of therapeutics. They systematically consider the intracellular signal transduction pathways that respond to ECM mechanical cues and discuss the importance of cross talk. Drug targets and agents in the pipeline are reviewed, highlighting late-stage failures in phase II/III of zinpentraxin alfa (recombinant human pentraxin) and zirtaxesat (autotaxin inhibitor) in idiopathic pulmonary fibrosis. Early-stage preclinical developments targeting mechanosensing pathways were also discussed. The contrast made in inflammation and ageing between the lung and the ovary presents a fascinating insight and potentially offers a useful paradigm for identification of novel anti-ageing approaches. The concept of fibrosis and longevity has been brought into sharp focus by a report showing that neutralisation of interleukin-11 from middle age in mice prolongs life by ~25% (Widjaja et al., 2024). Time will tell whether the elusive elixir of life is to be found by manipulating interleukin-11 levels or activity. Alastair G. Stewart: Conceptualization (lead); writing—original draft (lead). Xumei Gao: writing—review and editing. Work in the authors' laboratory has been supported by NHMRC Grant 118637, ARC CPTT Grant IC170100016, Graeme Clark Institute and Tianli Biotech. A.G.S. and X.G. are co-inventors on biosensor and fluidics technology relevant to the content of this article.