Hyaluronic Acid: Molecular Weight, CD44, and Why It Is Not Simply a Moisturiser
Executive summary
Hyaluronic acid (HA) is marketed as a straightforward hydrating ingredient. Biologically it is more than that: it is a signalling molecule whose effects depend on its molecular weight.
This note explains that high-molecular-weight HA and low-molecular-weight HA behave very differently, and that the body generates low-molecular-weight fragments in damaged or inflamed tissue.
It describes CD44, the principal cell-surface receptor for HA, and the signalling that HA sets off when it binds.
It sets out, carefully, what the cancer literature does and does not say about HA and CD44, and where the boundary of the evidence lies.
It asks what this means for a cosmetic serum whose molecular weight you cannot see on the label.
It closes on the more basic question of whether topical HA is needed at all, given that the skin produces its own.
I have no commercial interest in any HA product, and I do not sell skincare.
Introduction
Hyaluronic acid is one of the most heavily promoted ingredients in modern skincare, almost always on a single claim: that it holds water, and therefore hydrates. That claim is not false, but it is a small part of a larger biological picture, and the larger picture is routinely left off the bottle. HA is not an inert sponge. It is a molecule the body uses to send signals between cells, and the signal it sends depends on its size.
I should be clear at the outset about what I am and am not arguing, because this topic is easy to misrepresent. I am not claiming that a hyaluronic acid serum causes cancer. I am making a narrower and, I think, more defensible point: HA is biologically active in a way that depends on its molecular weight, one of the receptors it acts through is deeply involved in tumour biology, and the marketing premise that HA is a simple, inert hydrator does not survive contact with the science. I trained in dentistry, then in dermatology and separately in anti-aging medicine and in metabolic medicine, and I have taught the biology of the extracellular matrix to clinicians. I have no financial interest in any skincare product.
What hyaluronic acid actually is
HA is a glycosaminoglycan, a long sugar chain, and it is one of the most abundant components of the extracellular matrix, the scaffolding between cells. The body makes it continuously through a family of enzymes called hyaluronan synthases, and in the skin the cells that produce it are the fibroblasts of the dermis. Crucially, the body makes it at a controlled size, in the right place, in the right amount. Its native, freshly synthesised form is a very long, high-molecular-weight chain.
This matters because the size is not incidental. It is, in effect, part of the message.
Molecular weight determines what HA does
The single most important fact about HA, and the one skincare marketing omits, is that high-molecular-weight HA (HMW-HA) and low-molecular-weight HA (LMW-HA) do close to opposite things. According to research retrieved from PubMed, native HMW-HA tends to be anti-inflammatory and immunomodulatory, while the shorter LMW-HA fragments are potent pro-inflammatory signals; the size of the molecule effectively sets the balance between the two (Ref 1). The same reviews describe how those long chains are broken down into short fragments in the first place: in damaged, infected or inflamed tissue, enzymes called hyaluronidases and reactive oxygen species chop HMW-HA into LMW-HA (Ref 1, Ref 5).
A useful way to picture this is that the length of the chain is a status report. A long, intact chain signals "tissue is healthy and quiet." A field of short fragments signals "tissue has been damaged," and the cell responds accordingly. The molecule is not just occupying space and holding water; it is telling the cells around it what state the neighbourhood is in.
I should be honest that this picture, while well supported, is not perfectly uniform. At least one study found that HA of various molecular weights did not activate macrophages as the pro-inflammatory model would predict (Ref 6). I would not lean on that result too heavily, though, given how it was produced: it used immortalised mouse macrophage cell lines rather than primary human cells, examined a single cell type through a narrow set of readouts, and was conducted entirely in a dish. Cell lines are convenient, but they do not always behave like the living tissue they are standing in for. The size-dependent story remains the mainstream reading of the evidence; I include this dissenting result because leaving it out would be dishonest, not because I think it overturns the picture.
CD44: the receptor that reads the signal
For a signal to be received, there must be a receptor. HA has several, but the principal one is a cell-surface protein called CD44. It sits in the membrane like a sensor on the outside wall of the cell, and when HA binds to it, it triggers changes on the inside. According to work retrieved from PubMed, HA is the main ligand for CD44, and that binding activates signalling pathways that drive cell proliferation, improve cell survival, reorganise the internal skeleton of the cell and increase cell movement (Ref 2). HA also engages other receptors, including the toll-like receptors and RHAMM, which is part of why its effects are so context-dependent.
The point worth holding onto is the one Dr Abs's critics missed when this was discussed on video: HA is a signal, and CD44 is how the cell reads it. Treating HA as though it were a passive humectant ignores the entire receptor biology.
What the cancer literature does, and does not, say
This is the part that needs stating precisely, because it is the part most easily distorted. The involvement of the HA-CD44 axis in cancer is not fringe speculation; it is a substantial, mainstream body of work. According to reviews retrieved from PubMed, HA is often enriched in tumours, in some tumour types the amount of HA present tracks with how malignant the tumour is, and HA-CD44 binding activates intracellular signalling (including Rho-family GTPase pathways) that promotes tumour-cell adhesion, growth, survival, migration and invasion (Ref 4). CD44 itself is one of the best-known markers of cancer stem cells, and its signalling is linked to metastasis and to the epithelial-to-mesenchymal transition that lets tumour cells spread (Ref 3). Separately, the fragmentation of HMW-HA into LMW-HA in the tumour environment is associated with the breakdown of the barrier between blood vessels and tissue, a step in angiogenesis and metastasis (Ref 5).
Now the necessary caveats, because they are what separate an honest account from a scare story. First, much of this evidence comes from cell lines and animal models and from the study of established tumours; it describes what HA and CD44 do inside cancer biology, not what a cosmetic ingredient does to healthy skin. Second, the literature is not tidy: one of the CD44 reviews notes openly that there are contradictory findings on whether high or low CD44 expression predicts a worse outcome (Ref 3). Third, and most importantly, none of this demonstrates that applying an HA serum to intact skin causes cancer, and I want to be unambiguous that I am not claiming it does. Whether cosmetic HA even penetrates living skin in a way that engages these receptors at all is itself an open question.
I want to address directly the way this argument has been misrepresented, because it matters. I have never said that hyaluronic acid causes cancer. I have said something quite different and quite precise: that HA is a molecular-weight-dependent signalling molecule, that its low-molecular-weight fragments act through receptors such as CD44, and that this same receptor system is deeply involved in tumour biology. Those are not the same statement, and collapsing the second into the first is not a paraphrase, it is a failure to read. It is the difference between saying a molecule participates in signalling pathways relevant to cancer and saying the molecule gives you cancer, and anyone who cannot hold that distinction has no business summarising a scientific argument for other people. The precision of the words is not pedantry here, it is the entire point. If you are going to quote a clinician on cancer biology, the least you owe your readers is to represent what was actually said, rather than the cartoon of it that is easier to be outraged by.
What the evidence does establish is narrower and still meaningful: HA is a size-dependent, receptor-active signalling molecule, and one of those receptors is central to tumour progression. That is a long way from "it just holds water."
What this means for a bottle of serum
Return, then, to the cosmetic product. If HA's biological effect depends on its molecular weight and its conformation, the obvious question is: what molecular weight is in the bottle? In practice, you usually cannot tell. Labels advertise the presence of hyaluronic acid; they rarely specify the size distribution, the conformational state, or the purity, and there is no reason to assume it matches the finely controlled material the body makes for itself. My point is not that this is proven to be harmful. My point is that the premise underpinning the whole category, that HA is a simple, inert, water-binding ingredient, is not a premise the biology supports, and a molecule with this much signalling activity deserves more scrutiny than a marketing line allows.
Do you need it at all?
There is a more basic question underneath all of this. The skin already makes its own HA, at the right size and in the right place, through its fibroblasts. If those cells are working well, the requirement to apply more from outside is not obvious. If they are not working well, then adding a single molecule to the surface does not address why they have stopped, and it is unlikely that HA is the only thing they have stopped producing.
My own clinical preference, and I put it as a preference rather than a proven prescription, is to focus on the conditions that let skin cells function properly, rather than on layering individual finished molecules onto the surface. The details of that are a separate topic. The narrower conclusion of this note stands on its own: hyaluronic acid is a signalling molecule whose behaviour depends on its size, not the passive moisturiser it is sold as.
Conclusion
Hyaluronic acid is genuinely interesting biology, and that is precisely why the "just adds water" framing is inadequate. High- and low-molecular-weight HA do different, sometimes opposing things; the body generates the pro-inflammatory short fragments when tissue is damaged; CD44 and related receptors read those signals; and the HA-CD44 axis is woven through tumour biology. None of that means a serum causes cancer, and I have been careful not to say so. It does mean that a molecule this active should not be treated as inert, and that the confidence of the marketing is not matched by the caution of the science.
Disclosures
I have no commercial interest in any hyaluronic acid product or skincare brand. I offer private consultations for those who want to discuss their own situation, though for most people a good, regular relationship with a local clinician is worth more than any single consultation with me.
References
Identified and verified via PubMed; DOI links included.
Hoarau A, Polette M, Coraux C. Lung Hyaluronasome: Involvement of Low Molecular Weight HA (LMW-HA) in Innate Immunity. Biomolecules, 2022. https://doi.org/10.3390/biom12050658
Chen C, Zhao S, Karnad A, Freeman JW. The biology and role of CD44 in cancer progression: therapeutic implications. Journal of Hematology & Oncology, 2018. https://doi.org/10.1186/s13045-018-0605-5
Hassn Mesrati M, Syafruddin SE, Mohtar MA, Syahir A. CD44: A Multifunctional Mediator of Cancer Progression. Biomolecules, 2021. https://doi.org/10.3390/biom11121850
Bourguignon LYW. Hyaluronan-mediated CD44 activation of RhoGTPase signaling and cytoskeleton function promotes tumor progression. Seminars in Cancer Biology, 2008. https://doi.org/10.1016/j.semcancer.2008.03.007
Singleton PA. Hyaluronan regulation of endothelial barrier function in cancer. Advances in Cancer Research, 2014. https://doi.org/10.1016/B978-0-12-800092-2.00007-1
Krejcova D, Pekarova M, Safrankova B, Kubala L. The effect of different molecular weight hyaluronan on macrophage physiology. Neuro Endocrinology Letters, 2009 (contradictory result: LMW-HA did not activate macrophages). https://pubmed.ncbi.nlm.nih.gov/20027154/
